Disubstituted octahydropyrrolo[3,4-c]pyrroles as orexin receptor modulators

ABSTRACT

Disubstituted octahydropyrrolo[3,4-c]pyrrole compounds are described, which are useful as orexin receptor modulators. Such compounds may be useful in pharmaceutical compositions and methods for the treatment of diseased states, disorders, and conditions mediated by orexin activity, such as insomnia.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/601,832, filed Oct. 15, 2019, which is a continuation of U.S. patentapplication Ser. No. 15/413,965, filed Jan. 24, 2017, which is acontinuation of U.S. patent application Ser. No. 14/734,225, filed Jun.9, 2015, which is a continuation of U.S. patent application Ser. No.14/138,941, filed Dec. 23, 2013, which is a continuation of U.S. patentapplication Ser. No. 13/503,231, filed Apr. 20, 2012, which is anational stage under 35 U.S.C. 371 of International Patent ApplicationNo. PCT/US2010/053606, filed Oct. 21, 2010, which claims benefit ofpriority under 35 U.S.C. § 119(e) of U.S. Provisional Patent ApplicationNo. 61/254,509 filed Oct. 23, 2009, the disclosures of which are herebyincorporated by reference in their entirety.

TECHNICAL FIELD

The present invention relates to certain disubstitutedoctahydropyrrolo[3,4-c]pyrrole compounds, pharmaceutical compositionscontaining them, methods of making them, and methods of using them forthe modulation of the orexin receptor and for the treatment of diseasestates, disorders, and conditions mediated by orexin receptor activity.

BACKGROUND

Orexin (or hypocretin) signaling is mediated by two receptors and twopeptide agonists. The two orexin peptides (orexin A and orexin B) hereinafter referred to as orexins, bind to two high affinity receptors,termed orexin-1 and orexin-2 receptors. The orexin-1 receptor isselective in favor of orexin A, while the orexin-2 receptor binds bothorexins with similar affinities. The orexins are cleavage products ofthe same gene, prepro orexin. In the central nervous system neuronsexpressing prepro-orexin, the precursor from which orexin is produced,are found in the perifornical nucleus, the dorsal hypothalamus and thelateral hypothalamus (C. Peyron et al., J. Neurosci., 1998, 18(23),9996-10015). Orexinergic cells in these nuclei project to many areas ofthe brain, extending rostrally to the olfactory bulbs and caudally tothe spinal cord (van den Pol, A. N. et al., J. Neuroscience., 1999,19(8), 3171-3182).

The broad CNS distribution of orexin projections and neurons expressingorexin receptors is suggestive of orexin involvement in a number ofphysiological functions including; feeding, drinking, arousal, stress,reward, metabolism and reproduction (T. Sakurai, Nature ReviewsNeuroscience, 2007, 8(3), 171-181).

The targeted necrosis of cells expressing prepro-orexin suggests themost physiologically important roles of the orexins are likely to beeffects on arousal, feeding and metabolism (J. Hara et al., Neuron,2001, 30, 345-354). A prominent orexin neuronal projection via the vagusnerve probably mediates central orexin effects on cardiac parameters (W.K. Samson et al., Brain Res., 1999, 831, 248-253; T. Shirasaka et al.,Am. J. Physiol., 1999, 277, R1780-R1785; C.-T. Chen et al., Am. J.Physiol., 2000, 278, R692-R697), gastric acid secretion and gastricmotility (A. L. Kirchgessner and M.-T. Liu, Neuron, 1999, 24, 941-951;N. Takahashi et al., Biochem. Biophys. Res. Commun., 1999, 254,623-627).

Several lines of evidence indicate that the orexin system is animportant modulator of arousal. Rodents administered orexinsintracerebroventricularly spend more time awake (Piper et al., J.Neurosci. 2000, 12, 726-730). Orexin-mediated effects on arousal havebeen linked to orexin neuronal projections to histaminergic neurons inthe tuberomammillary nucleus (TMN) (Yamanaka et al., Biochem. Biophys.Res. Comm. 2002, 290, 1237-1245). TMN neurons express the orexin-2receptor primarily, and the orexin-1 receptor to a lesser extent.Rodents whose prepro orexin gene has been knocked out, or whoseorexigenic neurons have been lesioned, display altered sleep/wake cyclessimilar to narcolepsy (Chemelli et al., Cell 1999, 98, 437-451; Hara etal., 2001, supra). Dog models of narcolepsy have been shown to havemutant or non-functional orexin-2 receptors (Lin et al., Cell 1999, 98,365-376). Human narcolepsy appears to be linked to deficient orexinsignaling, likely related to immune ablation of orexinergic neurons inthe lateral hypothalamus (Mignot et al., Am. J. Hum. Genet. 2001, 68:686-699; Minot & Thorsby, New England J. Med. 2001, 344, 692), or, inrare cases, to mutations in the orexin-2 gene (Peyron et al., NatureMed. 2000, 6, 991-997). The disclosure that rats, dogs and humanstreated with the dual orexin-1/2 receptor antagonist, ACT-078573(Brisbare-Roch et al., Nature Medicine, 2007, 13, 150-155) exhibiteddecreased alertness together with characteristic clinical and EEG(electroencephalographic) signs of sleep provides evidence to support arole for the orexin system in the regulation of arousal, sleep and wakestates. EEG data indicates that orexin-2 may be more important thanorexin-1 in the modulation of sleep/wake (P. Malherbe et al., MolecularPharmacology (2009) 76(3):618-31; C. Dugovic et al., J. Pharmacol. Exp.Ther., 2009, 330(1), 142-151). Disorders of the sleep-wake cycle aretherefore likely targets for orexin-2 receptor antagonist therapy.Examples of such disorders include sleep-wake transition disorders,insomnia, restless legs syndrome, jet-lag, disturbed sleep, and sleepdisorders secondary to neurological disorders (e.g., manias,depressions, manic depression, schizophrenia, and pain syndromes (e.g.,fibromyalgia, neuropathic pain).

The orexin system also interacts with brain dopamine systems.Intracerebroventricular injections of orexins in mice increase locomotoractivity, grooming and stereotypy; these behavioral effects are reversedby administration of D₂ dopamine receptor antagonists (Nakamura et al.,Brain Research, 873(1), 181-7). Therefore, orexin-2 modulators may beuseful to treat various neurological disorders; e.g., agonists orup-regulators to treat catatonia, antagonists or down-regulators totreat Parkinson's disease, Tourette's syndrome, anxiety, delirium anddementias.

Recent evidence indicates a role for orexin in the pathogenesis ofAlzheimer's disease (Kang et al, Science Express, 2009, 1-10). Braininterstitial fluid levels of amyloid-beta were demonstrated to fluctuatediurnally in both humans and rodents with sleep deprivation in rodentsleading to significant increases in brain interstitial fluid levels ofamyloid-beta. Infusion of a dual orexin antagonist in rodents suppressedinterstitial levels of amyloid-beta and abolished the natural diurnalvariation of amyloid-beta. The reduction of interstitial fluidamyloid-beta levels is correlated with reduced amyloid plaque formation,a hallmark of Alzheimer's disease, and consequently the regulation ofsleep time could potentially inhibit amyloid-beta aggregation and slowthe progression of Alzheimer's disease.

Orexin neurons project to many regions of the brain associated withreward function (T. Sakurai, supra) and research, focusing on animalmodels of drug intake, reward, and reinstatement, has expanded the linkbetween the orexin system and addiction. A comprehensive set of datasuggest that drugs of abuse activate the orexin system, which in turnenhances drug reward or drug seeking (G. Aston-Jones et al.,Neuropharmacology, 2009, 56 (Suppl 1) 112-121. Thus interactions betweennicotine (J. K. Kane et al., Endocrinology, 2000, 141(10), 3623-3629; J.K. Kane et al., Neurosci. Lett., 2001, 298(1), 1-4), morphine (D.Georgescu, et al., J. Neurosci., 2003, 23(8), 3106-3111) and amphetamine(C. J. Winrow et al., Neuropharmacology, 2010, 58(1), 185-94) and theorexin system have been demonstrated. Additional studies from a numberof laboratories have demonstrated an important relationship between theOrexin system and ethanol consumption. As examples, ethanol consumptionin an alcohol-preferring strain of rat was shown to up regulate OrexinmRNA in the lateral hypothalamus and that an Orexin-1 receptorantagonist reduced operant responding for ethanol (Lawrence, et. al.,Br. J. Pharmacol., 2006, 148, 752-759). Treatment with an orexin-1antagonist has also been shown to decrease operant responding forethanol (Richards, et. al., Psychopharmacology, 2008, 199 (1), 109-117).Other studies have demonstrated increased Fos activation of orexinneurons following contextual reinstatement to ethanol seeking (Dayas,et. al., Biol. Psychiatry, 2008, 63 (2), 152-157 and Hamlin, et. al.,Neuroscience, 2007, 146, 525-536). Studies have also shown increasedethanol consumption following Orexin infusion into the paraventricularnucleus of the hypothalamus or in the lateral hypothalamus (Schneider,et. al., Alcohol. Clin. Exp. Res., 2007, 31(11), 1858-1865). Thesestudies provide evidence that modulation of the Orexin system effectsalcohol preference and therefore Orexin receptor antagonists are likelyto be useful for the treatment of alcoholism.

Orexins and their receptors have been found in both the myenteric andsubmucosal plexus of the enteric nervous system, where orexins have beenshown to increase motility in vitro (Kirchgessner & Liu, Neuron 1999,24, 941-951) and to stimulate gastric acid secretion in vitro (Takahashiet al., Biochem. Biophys. Res. Comm. 1999, 254, 623-627). Orexinmediated effects on the gut may be driven by a projection via the vagusnerve (van den Pol, 1999, supra), as vagotomy or atropine prevent theeffect of an intracerebroventricular injection of orexin on gastric acidsecretion (Takahashi et al., 1999, supra). Orexin receptor antagonistsor other down-regulators of orexin receptor-mediated systems aretherefore potential treatments for ulcers, irritable bowel syndrome,diarrhea and gastroesophageal reflux.

Body weight may also be affected by orexin-mediated regulation ofappetite and metabolism (T. Sakurai et al., Cell, 1998, 92(4), 573-585;T. Sakurai, Reg. Pept., 1999, 85(1), 25-30). Some effects of orexin onmetabolism and appetite may be mediated in the gut, where, as mentioned,orexins alter gastric motility and gastric acid secretion. Orexinreceptor antagonists therefore are likely to be useful in treatment ofoverweight or obesity and conditions related to overweight or obesity,such as insulin resistance, type II diabetes, hyperlipidemia,gallstones, angina, hypertension, breathlessness, tachycardia,infertility, sleep apnea, back and joint pain, varicose veins andosteoarthritis. Conversely, orexin receptor agonists are likely to beuseful in treatment of underweight and related conditions such ashypotension, bradycardia, amenorrhea and related infertility, and eatingdisorders such as anorexia and bulimia.

Intracerebroventricularly administered orexins have been shown toincrease mean arterial pressure and heart rate in freely moving (awake)animals (Samson et al., Brain Res. 1999, 831, 248-253; Shirasaka et al.,Am. J. Physiol. 1999, 277, R1780-R1785) and in urethane-anesthetizedanimals (Chen et al., Am. J. Physiol. 2000, 278, R692-R697), withsimilar results. Orexin receptor agonists may therefore be candidatesfor treatment of hypotension, bradycardia and heart failure relatedthereto, while orexin receptor antagonists may be useful for treatmentof hypertension, tachycardia and other arrhythmias, angina pectoris andacute heart failure.

From the foregoing discussion, it can be seen that the identification oforexin receptor modulators, in one embodiment modulators of the orexin-2receptor, will be of great advantage in the development of therapeuticagents for the treatment of a wide variety of disorders that aremediated through these receptor systems.

Citation of a reference herein shall not be construed as an admissionthat such reference is prior art to the present invention. Allpublications referred to herein are incorporated by reference in theirentireties.

Various small-molecule orexin receptor modulators have been reportede.g., N-aroyl cyclic amine derivatives (International Publication No.WO2003002561, Jan. 9, 3003), ethylene diamine derivatives (InternationalPublication No. WO2003051872, Jun. 26, 2003), sulfonylamino-acetic acidderivatives (International Publication No. WO2004033418, Apr. 22, 2004),N-aryl acetyl cyclic amine derivatives (International Publication No.WO2004041791, May 21, 2004), diazepan derivatives (InternationalPublication No. WO2007126935, Nov. 8, 2007), amidoethylthioetherderivatives (International Publication No. WO2007126934, Nov. 8, 2007),2-substituted proline bis-amide derivatives (International PublicationNo. WO2008008551, Jan. 17, 2008), bridged diazepan derivatives(International Publication No. WO2008008517, Jan. 17, 2008), substituteddiazepan derivatives (International Publication No. WO2008008518, Jan.17, 2008; US20080132490, WO2009058238), oxo bridged diazepan derivatives(International Publication No. WO2008143856, Nov. 27, 2008), 1,2-diamidoethylene derivatives (International Publication No. WO2009022311, Feb.19, 2009), heteroaryl derivatives (International Publication No.WO20090163485, Jun. 25, 2009), methyl substituted piperidinylderivatives (International Publication No. WO2009124956, Oct. 15, 2009),N,N-disubstituted-1,4-diazepane derivatives (Cox et al, Bioorganic &Medicinal Chemistry Letters, 2009, 19(11), 2997-3001), Orexin/Hypocretinreceptor ligands (Boss, et al., Journal of Medicinal Chemistry, 2009,52(4), 891-903) 3,9-diazabicyclo[4.2.1]nonanes (Coleman et al,Bioorganic & Medicinal Chemistry Letters, 2010, 20(14), 4201-4205), thedual orexin receptor antagonist,[(7R)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone,(Cox, et. al., Journal of Medicinal Chemistry, 2010 53(14) 5320-5332),pyridazine carboxamide derivatives (International Publication No.WO2010051238), 2,5-disubstituted benzamide derivatives (InternationalPublication No WO2010051237, May 6, 2010), isonicotinamides(International Publication No WO2010051236),heterocyclylbenzoylpiperazines derivatives (International Publication NoWO201048012), substituted diazepane derivatives (InternationalPublication No WO2010048017), substituted pyrrolidine derivatives(International Publication No WO2010048014), triazolylbenzoylpiperidinederivatives (International Publication No WO2010048010),triazolylbenzoylmorpholine derivatives (WO2010048013), conformationallyrestrained N,N disubstituted 1,4-diazapane derivatives (Coleman et al,Bioorganic & Medicinal Chemistry Letters, 2010, 20(7), 2311-2315),tripyridyl carboxamide derivatives (International Publication NoWO2010017260), imidazopyridylmethyl substituted piperidine derivatives(International Publication No WO2010072722), imidazopyrazine substitutedpiperidine derivatives (US2010160344, Jun. 24, 2010; US20100160345, Jun.24, 2010; International Publication No WO2010060472, Jun. 3, 2010),N-{[(1R,4S,6R)-3-(2-pyridinylcarbonyl)-3-azabicyclo[4.1.0]hept-4-yl]methyl}-2-heteroarylaminederivatives (International Publication No WO2010063663),N-{[(1S,4S,6S)-3-(2-pyridinylcarbonyl)-3-azabicyclo[4.1.0]hept-4-yl]methyl}-2-heteroarylaminederivatives (International Publication No WO2010063662),imidazopyrimidine derivatives (International Publication NoWO2010060471), and imidazopyrazine derivatives (InternationalPublication No WO2010060470). There remains a need, however, for potentorexin receptor modulators with desirable pharmaceutical properties.

Substituted diaza-bicyclic compounds have been reported as activecentral nervous system agents (International Publication No.WO2001081347, Nov. 1, 2001; US2002/0019388, Feb. 14, 2002), α7acetylcholine receptor modulators (US2005/101602, May 12, 2005;US2005/0065178, Mar. 24, 2005 and Frost et al, Journal of MedicinalChemistry, 2006, 49(26), 7843-7853), proline transporter inhibitors forthe treatment of cognitive impairment (WO2008067121, Jun. 5, 2008) andfor improving cognition (WO 2006 124897, Nov. 23, 2006 andUS20060258672, Nov. 16, 2006), as androgen receptor ligands for thetreatment of androgen receptor associated conditions including cancer(WO2009081197, Jul. 2, 2009), and as histone deacetylase inhibitors forthe treatment of cancers, neurodegenerative diseases and autoimmunediseases (WO20060123121, Nov. 23, 2006).

SUMMARY

Certain disubstituted octahydropyrrolo[3,4-c]pyrrole derivatives havebeen found to have orexin-modulating activity. Thus, the invention isdirected to the general and preferred embodiments defined, respectively,by the independent and dependent claims appended hereto, which areincorporated by reference herein.

In one general aspect, the invention is directed to a chemical entity ofFormula (I):

wherein:R¹ is a member selected from the group consisting of:

-   -   A) phenyl substituted or unsubstituted with one or two R^(a)        members, and substituted in the ortho position with R^(b);        -   R^(a) is independently selected from the group consisting            of: —H, halo, —C₁₋₄alkyl, —C₁₋₄alkoxy, and —NO₂, wherein two            adjacent R^(a) members may come together to form a six            membered aromatic ring;        -   R^(b) is a member selected from the group consisting of:            -   a) halo, —C₁₋₄alkoxy, —C₁₋₄alkyl, —CF₃, —OCF₃, or —CN;            -   b) 5-membered heteroaryl ring containing one oxygen or                one sulfur members;            -   c) 5-6 membered heteroaryl ring containing one, two or                three nitrogen members, optionally containing one oxygen                member, substituted or unsubstituted with halo or                —C₁₋₄alkyl; and            -   d) phenyl substituted or unsubstituted with halo, —CH₃,                or —CF₃;    -   B) pyridine substituted or unsubstituted with one or two R^(c)        members and substituted with R^(d), wherein R^(d) is positioned        adjacent to the point of attachment by R¹;        -   R^(c) is C₁₋₄alkyl;        -   R^(d) is a member selected from the group consisting of:            -   a) 5-6 membered heteroaryl ring selected from the group                consisting of: 1H-1,2,3-triazol-1-yl,                2H-1,2,3-triazol-2-yl, 1H-pyrazol-5-yl,                3-methyl-1,2,4-oxadiazol-5-yl, pyridinyl,                3-methyl-pyridin-2-yl;                1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl), phenyl,                and pyrimidin-2-yl; and            -   b) —CF₃, —Br, and —C₁₋₄alkoxy;    -   C) 5-membered heteroaryl ring selected from the group consisting        of: 2-methyl-1,3-thiazol-yl, 1H-pyrazol-5-yl, oxazole,        isoxazolyl, thiophen-2-yl, and furan-2-yl, each substituted with        phenyl substituted or unsubstituted with —F; and    -   D) 5-13 membered aryl or heteroaryl ring selected from the group        consisting of: 3-methylfuran-2-yl, 9H-fluorene, quinoline,        cinnoline; 3-(1H-pyrrol-1-yl)thiophen-2-yl,        8-[1,2,3]-triazol-2-yl-naphthalen-1-yl,        2,3-dihydro-1,4-benzodioxin-5-yl, 1H-indol-7-yl,        4-fluoronaphthalen-1-yl, and naphthalen-1-yl;        R² is a member selected from the group consisting of:    -   A) 6-membered heteroaryl ring containing two nitrogen members        substituted with one or more members independently selected from        the group consisting of: halo, —C₁₋₄alkyl, —CD₃, -D,        —C₁₋₄alkoxy, cyclopropyl, morpholin-2-yl, —CO₂C₁₋₄alkyl, —CO₂H,        —CH₂OH, —C(O)N(C₁₋₄alkyl)₂, —CF₃, —CN, —OH, —NO₂,        —N(C₁₋₄alkyl)₂, phenyl, furan-2-yl, thiophen-2-yl,        1H-pyrazol-4-yl, and pyrrolidin-1-yl;    -   B) pyridine substituted with one or two members independently        selected from the group consisting of: halo, —C₁₋₄alkyl,        —C₁₋₄alkoxy, and —CF₃;    -   C) 9-membered heteroaryl ring selected from the group consisting        of: benzooxazol-2-yl, 6-fluoro-1,3-benzothiazole,        1,3-benzothiazole, 6-methoxy-1,3-benzothiazole,        6-methyl-1,3-benzothiazole, 6-chloro-benzothiazol-2-yl, and        4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine;    -   D) 10-membered heteroaryl ring selected from the group        consisting of: quinoxalin-2-yl, 3-methylquinoxalin-2-yl,        6,7-difluoroquinoxalin-2-yl, 3-(trifluoromethyl)quinoxaline,        quinoline, 4-methylquinoline, and 6-fluoroquinazolin-2-yl; and    -   E) 4-methyl-1,3,5-triazin-2-yl or 2-methylpyrimidin-4(3H)-one.

In another general aspect, the invention is directed to a chemicalentity of Formula (II):

whereinR³ is phenyl substituted or unsubstituted with a member independentlyselected from the group consisting of: —C₁₋₄alkoxy, and phenyl; andR⁴ is a member selected from the group consisting of(5-trifluoromethyl)-pyridin-2-yl, (5-trifluoromethyl)-pyrimidin-2-yl,4,6-dimethylpyrimidin-2-yl, and quinoxalin-2-yl.

Further embodiments are provided by pharmaceutically acceptable salts ofcompounds of Formula (I) or Formula (II), pharmaceutically acceptableprodrugs of compounds of Formula (I) or Formula (II), andpharmaceutically active metabolites of compounds of Formula (I) orFormula (II).

In certain embodiments, the compound of Formula (I) or Formula (II) is acompound selected from those species described or exemplified in thedetailed description below.

In a further aspect, the invention relates to pharmaceuticalcompositions for treating a disease, disorder, or medical conditionmediated by orexin receptor activity, comprising an effective amount ofat least one chemical entity selected from compounds of Formula (I) orFormula (II), pharmaceutically acceptable salts of compounds of Formula(I) or Formula (II), pharmaceutically acceptable prodrugs of compoundsof Formula (I) or Formula (II), and pharmaceutically active metabolitesof Formula (I) or Formula (II).

Pharmaceutical compositions according to the invention may furthercomprise one or more pharmaceutically acceptable excipients.

In another aspect, the chemical embodiments of the present invention areuseful as orexin receptor modulators. Thus, the invention is directed toa method for modulating orexin receptor activity, including when suchreceptor is in a subject, comprising exposing orexin receptor to aneffective amount of at least one chemical entity selected from compoundsof Formula (I) or Formula (II), pharmaceutically acceptable salts ofcompounds of Formula (I) or Formula (II), pharmaceutically acceptableprodrugs of compounds of Formula (I) or Formula (II), andpharmaceutically active metabolites of compounds of Formula (I) orFormula (II).

In another aspect, the invention is directed to a method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by orexin receptor activity, comprising administeringto the subject in need of such treatment an effective amount of at leastone chemical entity selected from compounds of Formula (I) or Formula(II), pharmaceutically acceptable salts of compounds of Formula (I) orFormula (II), pharmaceutically acceptable prodrugs of compounds ofFormula (I) or Formula (II), and pharmaceutically active metabolites ofcompounds of Formula (I) or Formula (II). Additional embodiments ofmethods of treatment are set forth in the detailed description.

In another aspect, method of studying isotopically labeled compounds inmetabolic studies (preferably with ¹⁴C), reaction kinetic studies (with,for example ²H or ³H), detection or imaging techniques [such as positronemission tomography (PET) or single-photon emission computed tomography(SPECT)] including drug or substrate tissue distribution assays, or inradioactive treatment of patients. For example, an ¹⁸F or ¹¹C labeledcompound may be particularly preferred for PET or an I¹²³ for SPECTstudies.

An object of the present invention is to overcome or ameliorate at leastone of the disadvantages of the conventional methodologies and/or priorart, or to provide a useful alternative thereto. Additional embodiments,features, and advantages of the invention will be apparent from thefollowing detailed description and through practice of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a Powder X-Ray Diffraction of an exemplified compound X

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The invention may be more fully appreciated by reference to thefollowing description, including the following glossary of terms and theconcluding examples. For the sake of brevity, the disclosures of thepublications, including patents, cited in this specification are hereinincorporated by reference.

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me, which also may be structurally depicted by thesymbol, “/”), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and groups that in light of the ordinary skill in the art andthe teachings provided herein would be considered equivalent to any oneof the foregoing examples.

The term “alkoxy” includes a straight chain or branched alkyl group witha terminal oxygen linking the alkyl group to the rest of the molecule.Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,pentoxy and so on. “Aminoalkyl”, “thioalkyl”, and “sulfonylalkyl” areanalogous to alkoxy, replacing the terminal oxygen atom of alkoxy with,respectively, NH (or NR), S, and SO₂.

The term “cyano” refers to the group —CN.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkylgroups include the following entities, in the form of properly bondedmoieties:

A “heterocycloalkyl” refers to a monocyclic ring structure that issaturated or partially saturated and has from 4 to 7 ring atoms per ringstructure selected from carbon atoms and up to two heteroatoms selectedfrom nitrogen, oxygen, and sulfur. The ring structure may optionallycontain up to two oxo groups on sulfur ring members. Illustrativeentities, in the form of properly bonded moieties, include:

The term “aryl” refers to a monocyclic, or fused or spiro polycyclic,aromatic carbocycle (ring structure having ring atoms that are allcarbon) having from 3 to 12 ring atoms per ring. (Carbon atoms in arylgroups are sp² hybridized.) Illustrative examples of aryl groups includethe following moieties:

and the like.

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing entities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of heteroaryl,cycloalkyl, aryl and heterocycloalkyl groups listed or illustrated aboveare not exhaustive, and that additional species within the scope ofthese defined terms may also be selected.

The term “halogen” represents chlorine, fluorine, bromine or iodine. Theterm “halo” represents chloro, fluoro, bromo or iodo.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system. In cases where a specifiedmoiety or group is not expressly noted as being optionally substitutedor substituted with any specified substituent, it is understood thatsuch a moiety or group is intended to be unsubstituted.

The terms “para”, “meta”, and “ortho” have the meanings as understood inthe art. Thus, for example, a fully substituted phenyl group hassubstituents at both “ortho” (o) positions adjacent to the point ofattachment of the phenyl ring, both “meta” (m) positions, and the one“para” (p) position across from the point of attachment as illustratedbelow.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

The terms “buffered” solution or “buffer” solution are used hereininterchangeably according to their standard meaning. Buffered solutionsare used to control the pH of a medium, and their choice, use, andfunction is known to those of ordinary skill in the art. See, forexample, G. D. Considine, ed., Van Nostrand's Encyclopedia of Chemistry,p. 261, 5^(th) ed. (2005), describing, inter alia, buffer solutions andhow the concentrations of the buffer constituents relate to the pH ofthe buffer. See also Handbook of Chemistry and Physics, 84^(th) ed., pp.8-37 to 8-44. For example, a buffered solution is obtained by addingMgSO₄ and NaHCO₃ to a solution in a 10:1 w/w ratio to maintain the pH ofthe solution at about 7.5.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers.

The symbols

and

are used as meaning the same spatial arrangement in chemical structuresshown herein. Analogously, the symbols

and

are used as meaning the same spatial arrangement in chemical structuresshown herein.

Additionally, any formula given herein is intended to refer also tohydrates, solvates, and polymorphs of such compounds, and mixturesthereof, even if such forms are not listed explicitly. Certain compoundsof Formula (I) or Formula (II) or pharmaceutically acceptable salts ofcompounds of Formula (I) or Formula (II) may be obtained as solvates.Solvates include those formed from the interaction or complexation ofcompounds of the invention with one or more solvents, either in solutionor as a solid or crystalline form. In some embodiments, the solvent iswater and then the solvates are hydrates. In addition, certaincrystalline forms of compounds of Formula (I) or Formula (II) orpharmaceutically acceptable salts of compounds of Formula (I) or Formula(II) may be obtained as co-crystals. In certain embodiments of theinvention, compounds of Formula (I) or Formula (II) were obtained in acrystalline form. In other embodiments, crystalline forms of compoundsof Formula (I) or Formula (II) were cubic in nature. In otherembodiments, pharmaceutically acceptable salts of compounds of Formula(I) or Formula (II) were obtained in a crystalline form. In still otherembodiments, compounds of Formula (I) or Formula (II) were obtained inone of several polymorphic forms, as a mixture of crystalline forms, asa polymorphic form, or as an amorphous form. In other embodiments,compounds of Formula (I) or Formula (II) convert in solution between oneor more crystalline forms and/or polymorphic forms.

Reference to a chemical entity herein stands for a reference to any oneof: (a) the actually recited form of such chemical entity, and (b) anyof the forms of such chemical entity in the medium in which the compoundis being considered when named. For example, reference herein to acompound such as R—COOH, encompasses reference to any one of, forexample, R—COOH_((s)), R—COOH_((sol)), and R—COO⁻ _((sol)). In thisexample, R—COOH_((s)) refers to the solid compound, as it could be forexample in a tablet or some other solid pharmaceutical composition orpreparation; R—COOH_((sol)) refers to the undissociated form of thecompound in a solvent; and R—COO⁻ _((sol)) refers to the dissociatedform of the compound in a solvent, such as the dissociated form of thecompound in an aqueous environment, whether such dissociated formderives from R—COOH, from a salt thereof, or from any other entity thatyields R—COO⁻ upon dissociation in the medium being considered. Inanother example, an expression such as “exposing an entity to compoundof formula R—COOH” refers to the exposure of such entity to the form, orforms, of the compound R—COOH that exists, or exist, in the medium inwhich such exposure takes place. In still another example, an expressionsuch as “reacting an entity with a compound of formula R—COOH” refers tothe reacting of (a) such entity in the chemically relevant form, orforms, of such entity that exists, or exist, in the medium in which suchreacting takes place, with (b) the chemically relevant form, or forms,of the compound R—COOH that exists, or exist, in the medium in whichsuch reacting takes place. In this regard, if such entity is for examplein an aqueous environment, it is understood that the compound R—COOH isin such same medium, and therefore the entity is being exposed tospecies such as R—COOH_((aq)) and/or R—COO⁻ _((aq)), where the subscript“(aq)” stands for “aqueous” according to its conventional meaning inchemistry and biochemistry. A carboxylic acid functional group has beenchosen in these nomenclature examples; this choice is not intended,however, as a limitation but it is merely an illustration. It isunderstood that analogous examples can be provided in terms of otherfunctional groups, including but not limited to hydroxyl, basic nitrogenmembers, such as those in amines, and any other group that interacts ortransforms according to known manners in the medium that contains thecompound. Such interactions and transformations include, but are notlimited to, dissociation, association, tautomerism, solvolysis,including hydrolysis, solvation, including hydration, protonation, anddeprotonation. No further examples in this regard are provided hereinbecause these interactions and transformations in a given medium areknown by any one of ordinary skill in the art.

In another example, a zwitterionic compound is encompassed herein byreferring to a compound that is known to form a zwitterion, even if itis not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI:27369 by the Chemical Entities ofBiological Interest (ChEBI) dictionary of molecular entities. Asgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion ⁺H₃NCH₂COO⁻. Zwitterions, zwitterionic compounds,inner salts and dipolar ions in the known and well established meaningsof these terms are within the scope of this invention, as would in anycase be so appreciated by those of ordinary skill in the art. Becausethere is no need to name each and every embodiment that would berecognized by those of ordinary skill in the art, no structures of thezwitterionic compounds that are associated with the compounds of thisinvention are given explicitly herein. They are, however, part of theembodiments of this invention. No further examples in this regard areprovided herein because the interactions and transformations in a givenmedium that lead to the various forms of a given compound are known byany one of ordinary skill in the art.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl,¹²⁵I, respectively. Such isotopically labeled compounds are useful inmetabolic studies (preferably with ¹⁴C), reaction kinetic studies (with,for example ²H or ³H), detection or imaging techniques [such as positronemission tomography (PET) or single-photon emission computed tomography(SPECT)] including drug or substrate tissue distribution assays, or inradioactive treatment of patients. In particular, an 18F or ¹¹C labeledcompound may be particularly preferred for PET or an I¹²³ for SPECTstudies. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements. Isotopically labeled compounds of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of the species for the same variableelsewhere in the formula, unless stated otherwise.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R², R³, R⁴, A, R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h),R^(i), R^(j), and R^(k), and any other generic substituent symbol usedherein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂, and S₃, this listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R², R³, R⁴, A, R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), R^(h),R^(i), R^(j), and R^(k), and any other generic substituent symbol usedherein.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≤N≤m, with m>n. Any disubstituent referred to herein is meantto encompass the various attachment possibilities when more than one ofsuch possibilities are allowed. For example, reference to disubstituent-A-B-, where A≠B, refers herein to such disubstituent with A attached toa first substituted member and B attached to a second substitutedmember, and it also refers to such disubstituent with A attached to thesecond substituted member and B attached to the first substitutedmember.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

Some embodiments are given by compounds of Formula (I) where R¹ isphenyl substituted with R^(a), where R^(a) is —F, —I, —Cl, —OCH₃,—OCH₂CH₃, —CH₃, —CH(CH₃)₂, —C(CH₃)₃ or —NO₂.

In some of these embodiments, R¹ is substituted phenyl wherein R^(b) isa —Br, —F, —I, —C₁₋₄alkyl, —OCH₃, —OCH₂CH₃, —CN, —CF₃, or —OCF₃.

In some of these embodiments, R¹ is phenyl substituted with R^(a),wherein R^(a) is —H, —F, —Cl, —CH₃, —C(CH₃)₃, —OCH₃, or —OCH₂CH₃, andR^(b) is —Br, —F, —I, —C₁₋₄alkyl, —OCH₃, —OCH₂CH₃, —CN, —CF₃, or —OCF₃.

In some of these embodiments, R¹ is substituted phenyl where R^(b) is2-thiophen-2-yl or 2-furan-2-yl.

In some of these embodiments, R¹ is substituted phenyl where R^(b) isphenyl, 3-chlorophenyl, 4-fluorophenyl, 3-fluorophenyl, 4-methylphenyl,or 4-trifluoromethylphenyl.

In some of these embodiments, R¹ is substituted phenyl where R^(b) is1H-pyrrol-1-yl, 1H-pyrazol-1-yl, 1H-pyrazol-5-yl, 1H-imidazol-2-yl,1-methyl-1H-imidazol-2-yl, 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl,2H-1,2,3-triazol-1-yl, 1H-1,2,4-triazol-5-yl, 2H-1,2,4-triazol-1-yl,2H-1,2,4-triazol-3-yl, 4H-1,2,4-triazol-3-yl, 4H-1,2,4-triazol-4-yl,1-methyl-1H-1,2,4-triazol-3-yl, 1-methyl-1H-1,2,4-triazol-5-yl or1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl.

In some of these embodiments, R¹ is substituted phenyl, where R^(b) ispyridin-2-yl, 3-chloropyridin-2-yl, 3-fluoropyridin-2-yl,3-methylpyridin-2-yl, 4-methylpyridin-2-yl, 5-methylpyridin-2-yl,6-methylpyridin-2-yl, 2-pyridin-3-yl, or 2-pyrimidin-2-yl.

In some of these embodiments, R¹ is substituted phenyl, where R^(b) is3-methyl-1,2,4-oxadiazol-5-yl or oxazol-2-yl.

In some of these embodiments, R¹ is phenyl substituted with R^(a), whereR^(a) is halo, —C₁₋₄alkyl, or —C₁₋₄alkoxy, and R^(b) is triazole orpyrimidine substituted or unsubstituted with halo or —C₁₋₄alkyl.

In some of these embodiments, R¹ is(1-methylethyl)-2-(2H-1,2,3-triazol-2-yl)phenyl,2-(1H-1,2,3-triazol-1-yl)phenyl, 2-(2H-1,2,3-triazol-2-yl)phenyl,2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl,2-methyl-6-(2H-1,2,3-triazol-2-yl)phenyl,3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl,3-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl,3-methoxy-2-(1H-1,2,3-triazol-1-yl)phenyl,3-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl,3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl,3-methyl-2-(1H-1,2,3-triazol-1-yl)phenyl,4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl,4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl,4-methoxy-2-(1H-1,2,3-triazol-2-yl)phenyl,4,5-dimethoxy-2-[1,2,3]triazol-1-yl-phenyl,4,5-dimethoxy-2-[1,2,3]triazol-2-yl-phenyl,5-[1,2,3]triazol-2-yl-benzo[1,3]dioxol-4-yl,5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl,5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl,5-iodo-2-(2H-1,2,3-triazol-2-yl)phenyl,5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl,5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl,1-[1,2,3]triazol-2-yl-naphthalen-2-yl, 2-(1H-1,2,4-triazol-1-yl)phenyl,2-(1H-1,2,4-triazol-5-yl)phenyl,2-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl,2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl,2-(4H-1,2,4-triazol-3-yl)phenyl, 2-(4H-1,2,4-triazol-4-yl)phenyl,2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl,3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl,2-fluoro-6-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl,4,5-difluoro-2-(4H-1,2,4-triazol-4-yl)phenyl),2-fluoro-6-pyrimidin-2-ylphenyl, 2-(pyrimidin-2-yl)pyridin-3-yl,3-fluoro-2-pyrimidin-2-ylphenyl, 4-fluoro-2-(pyrimidin-2-yl)phenyl,4-methoxy-2-(pyrimidin-2-yl)phenyl, 5-fluoro-2-pyrimidin-2-ylphenyl, or5-methyl-2-pyrimidin-2-ylphenyl.

Some embodiments are given by compounds of Formula (I) where R¹ issubstituted pyridine, where R^(d) is —CF₃, —Br, or —OCH₂CH₂CH₃.

In some of these embodiments, wherein R¹ is substituted pyridine, R^(d)is 1H-pyrazol-5-yl, 2H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl,4H-1,2,3-triazol-1-yl, 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl,3-methylpyridin-2-yl, or 3-methyl-1,2,4-oxadiazol-5-yl.

In some of these embodiments, wherein R¹ is substituted pyridine, R^(d)is 1H-pyrazol-5-yl, 2H-1,2,3-triazol-1-yl, or 2H-1,2,3-triazol-2-yl.

In some of these embodiments, wherein R¹ is 1-phenyl-1H-pyrazol-5-yl,3-phenylthiophen-2-yl, 3-phenylfuran-2-yl, 5-phenyl-1,3-oxazol-4-yl,5-phenylisoxazol-4-yl, 5-(2-fluorophenyl)-2-methyl-1,3-thiazol-4-yl,2-methyl-5-phenyl-thiazol-4-yl, or5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl.

Some embodiments are given by compounds of Formula (I), where R¹ is3-methylfuran-2-yl, 9H-fluorene, quinoline, cinnoline,3-(1H-pyrrol-1-yl)thiophen-2-yl, 8-[1,2,3]-triazol-2-yl-naphthalen-1-yl,2,3-dihydro-1,4-benzodioxin-5-yl, 1H-indol-7-yl,4-fluoronaphthalen-1-yl, and naphthalen-1-yl and R² is selected from thegroup consisting of 4,6-dimethylpyrimidin-2-yl, 4-phenyl-pyrimidin-2-yl,quinoxaline, or 4-methoxypyrimidin-2-yl.

Some embodiments are given by compounds of Formula (I), where R² ispyrimidine substituted with —F, —Cl, -D, —CD₃, —CH₃, ethyl, isopropyl,propyl, tert-butyl, —CF₃, —OCH₃, —N(CH₃)₂, —CN, —OH, —CH₂OH, —NO₂,—CO₂CH₃, —CO₂H, —C(O)N(CH₃)₂, phenyl, furan-2-yl, thiophen-2-yl,1H-pyrazol-4-yl, cyclopropyl, pyrrolidin-1-yl, or morpholin-4-yl.

In some of these embodiments, R² is 4,6-dimethylpyrimidin-2-yl,4,5-dimethylpyrimidin-2-yl, 4,6-dimethoxypyrimidin-2-yl,4-phenyl-pyrimidin-2-yl, 4-furan-2-ylpyrimidin-2-yl,4-methylpyrimidin-2-yl, 4-methoxypyrimidin-2-yl,4-thiophen-2-ylpyrimidin-2-yl, N,N,6-trimethyl-pyrimidin-4-amine,4-(trifluoromethyl)pyrimidin-2-yl, 4,5,6-trimethylpyrimidin-2-yl,4-(trifluoromethyl)pyrimidine-5-carboxylate,4-(trifluoromethyl)pyrimidine-5-carboxylic acid, 5-nitro-pyrimidin-2-yl,6-methylpyrimidine-4-carboxylic acid,N,N-dimethyl-4-(trifluoromethyl)pyrimidine-5-carboxamide,N,N,6-trimethylpyrimidine-carboxamide,6-methylpyrimidine-4-carbonitrile,4,6-bis(trifluoromethyl)pyrimidin-2-yl, 6-methyl-pyrimidin-4-ol,4-(furan-2-yl)-6-methylpyrimidin-2-yl, 5-fluoro-4-methylpyrimidin-2-yl,5-fluoropyrimidin-2-yl, 4-methoxy-6-methylpyrimidin-2-yl,4-ethyl-6-methylpyrimidin-2-yl, 4-isopropyl-6-methylpyrimidin-2-yl,4-tertbutyl-6-methylpyrimidin-2-yl,4-cyclopropyl-6-methylpyrimidin-2-yl,4-methyl-6-morpholin-4-ylpyrimidin-2-yl,5-chloro-4-methylpyrimidin-2-yl, 5-chloro-4,6-dimethylpyrimidin-2-yl,5-fluoro-4,6-dimethylpyrimidin-2-yl, 5-trifluoromethylpyrimidin-2-yl,4,6-bis[(²H3)methyl](²H)pyrimidin-2-yl, or5-ethyl-4,6-dimethylpyrimidin-2-yl.

In some of these embodiments, R² is pyrimidine substituted with one ormore —Cl, —F, —CH₃, —CF₃, —N(CH₃)₂, -D, or —CD₃.

In some of these embodiments, R² is 4,6-dimethylpyrimidin-2-yl,4,5-dimethylpyrimidin-2-yl, 4,6-dimethoxypyrimidin-2-yl,4-methylpyrimidin-2-yl, 4-methoxypyrimidin-2-yl,N,N,6-trimethyl-pyrimidin-4-amine, 4-(trifluoromethyl)pyrimidin-2-yl,4,5,6-trimethylpyrimidin-2-yl, 4,6-bis(trifluoromethyl)pyrimidin-2-yl,6-methyl-pyrimidin-4-ol, 5-fluoro-4-methylpyrimidin-2-yl,5-fluoropyrimidin-2-yl, 4-methoxy-6-methylpyrimidin-2-yl,5-chloro-4-methylpyrimidin-2-yl, 5-chloro-4,6-dimethylpyrimidin-2-yl,5-fluoro-4,6-dimethylpyrimidin-2-yl, 5-trifluoromethylpyrimidin-2-yl, or4,6-bis[(²H3)methyl](²H)pyrimidin-2-yl.

Some embodiments are given by compounds of Formula (I) where R² ispyrazine or triazine substituted with one or more —CH₃.

Some embodiments are given by compounds of Formula (I) where R² ispyridine substituted with one or more —F, —OCH₃, —OCH₂CH₃, —CH₃, or—CF₃.

In some of these embodiments, R² is benzooxazol-2-yl,2-methylpyrimidin-4(3H)-one and4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine and R¹ is phenyl,substituted in the ortho position with R^(b), where R^(b) is2H-1,2,3-triazol-2-yl, 2H-1,2,3-triazol-1-yl,3-methyl-1,2,4-oxadiazol-5-yl or 2-pyrimidin-2-yl.

Some embodiments are given by compounds of Formula (I) where R² isquinoxalin-2-yl, 3-methylquinoxalin-2-yl, 6,7-difluoroquinoxalin-2-yl,3-(trifluoromethyl)quinoxaline, 4-methylquinoline, or6-fluoroquinazolin-2-yl and R¹ is phenyl substituted in the orthoposition with R^(b), where R^(b) is 2H-1,2,3-triazol-2-yl,2H-1,2,3-triazol-1-yl, 3-methyl-1,2,4-oxadiazol-5-yl, or2-pyrimidin-2-yl.

Some embodiments are given by compounds of Formula (II) where R³ isbiphenyl or 2-methoxyphenyl and R⁴ is (5-trifluoromethyl)-pyridin-2-yl,(5-trifluoromethyl)-pyrimidin-2-yl, 4,6-dimethylpyrimidin-2-yl, orquinoxalin-2-yl.

Some embodiments are given by compounds of Formula (I) wherein R¹ is2-(1H-1,2,3-triazol-1-yl)phenyl, 2-(2H-1,2,3-triazol-2-yl)phenyl,2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl,2-methyl-6-(2H-1,2,3-triazol-2-yl)phenyl,3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl,3-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl,3-methoxy-2-(1H-1,2,3-triazol-1-yl)phenyl,3-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl,3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl,3-methyl-2-(1H-1,2,3-triazol-1-yl)phenyl,4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl,4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl,4-methoxy-2-(1H-1,2,3-triazol-2-yl)phenyl,4,5-dimethoxy-2-[1,2,3]triazol-1-yl-phenyl,4,5-dimethoxy-2-[1,2,3]triazol-2-yl-phenyl,5-chloro-2-(2H-1,2,3-triazol-2-yl)phenyl,5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl,5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl,5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl,2-(1H-1,2,4-triazol-1-yl)phenyl, 2-(1H-1,2,4-triazol-5-yl)phenyl,2-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl,2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl,2-(4H-1,2,4-triazol-3-yl)phenyl, 2-(4H-1,2,4-triazol-4-yl)phenyl,2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl,3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl,2-fluoro-6-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl,4,5-difluoro-2-(4H-1,2,4-triazol-4-yl)phenyl),2-fluoro-6-pyrimidin-2-ylphenyl, 2-(pyrimidin-2-yl)pyridin-3-yl,3-fluoro-2-pyrimidin-2-ylphenyl, 4-fluoro-2-(pyrimidin-2-yl)phenyl,4-methoxy-2-(pyrimidin-2-yl)phenyl, 5-fluoro-2-pyrimidin-2-ylphenyl, or5-methyl-2-pyrimidin-2-ylphenyl and R² is 4,6-dimethylpyrimidin-2-yl,4,5-dimethylpyrimidin-2-yl, 4,6-dimethoxypyrimidin-2-yl,4-methylpyrimidin-2-yl, 4-methoxypyrimidin-2-yl, N,N,6-trimethyl-pyrimidin-4-amine, 4-(trifluoromethyl)pyrimidin-2-yl,4,5,6-trimethylpyrimidin-2-yl, 4,6-bis(trifluoromethyl)pyrimidin-2-yl,6-methyl-pyrimidin-4-ol, 5-fluoro-4-methylpyrimidin-2-yl,5-fluoropyrimidin-2-yl, 4-methoxy-6-methylpyrimidin-2-yl,5-chloro-4-methylpyrimidin-2-yl, 5-chloro-4,6-dimethylpyrimidin-2-yl,5-fluoro-4,6-dimethylpyrimidin-2-yl, 5-trifluoromethylpyrimidin-2-yl, or4,6-bis[(²H3)methyl](²H)pyrimidin-2-yl.

Some embodiments are given by compounds of Formula (I) wherein R¹ is3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl,6-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl,4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl, or3-[1,2,3]triazol-2-yl-pyridin-2-yl and R² is 4,6-dimethylpyrimidin-2-yl,5-fluoro-4,6-dimethylpyrimidin-2-yl, or 5-fluoro-4-methylpyrimidin-2-yl.

Compounds of Formula (I) and Formula (II) and pharmaceuticallyacceptable salts thereof are used, alone or in combination with one ormore additional active ingredients, to formulate pharmaceuticalcompositions. A pharmaceutical composition therefore comprises aneffective amount of at least one a compound of Formula (I) and Formula(II) or a pharmaceutically acceptable salt thereof.

The invention includes also pharmaceutically acceptable salts of thecompounds of Formula (I) and Formula (II), preferably of those describedabove and of the specific compounds exemplified herein, and methods oftreatment using such salts.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) and Formula(II), that is non-toxic, biologically tolerable, or otherwisebiologically suitable for administration to the subject. See, generally,G. S. Paulekuhn, et al., “Trends in Active Pharmaceutical IngredientSalt Selection based on Analysis of the Orange Book Database”, J. Med.Chem., 2007, 50:6665-72, S. M. Berge, et al., “Pharmaceutical Salts”, JPharm Sci., 1977, 66:1-19, and Handbook of Pharmaceutical Salts,Properties, Selection, and Use, Stahl and Wermuth, Eds., Wiley-VCH andVHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts arethose that are pharmacologically effective and suitable for contact withthe tissues of patients without undue toxicity, irritation, or allergicresponse. A compound of Formula (I) and Formula (II) may possess asufficiently acidic group, a sufficiently basic group, or both types offunctional groups, and accordingly react with a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

When the compound of Formula (I) or Formula (II) contains a basicnitrogen, the desired pharmaceutically acceptable salt may be preparedby any suitable method available in the art, for example, treatment ofthe free base with an inorganic acid, such as hydrochloric acid,hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid,phosphoric acid, and the like, or with an organic acid, such as aceticacid, phenylacetic acid, propionic acid, stearic acid, lactic acid,ascorbic acid, maleic acid, hydroxymaleic acid, isethionic acid,succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid,oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid,lauric acid, a pyranosidyl acid, such as glucuronic acid or galacturonicacid, an alpha-hydroxy acid, such as mandelic acid, citric acid, ortartaric acid, an amino acid, such as aspartic acid, glutaric acid/orglutamic acid, an aromatic acid, such as benzoic acid, 2-acetoxybenzoicacid, naphthoic acid, or cinnamic acid, a sulfonic acid, such aslaurylsulfonic acid, p-toluenesulfonic acid, methanesulfonic acid,ethanesulfonic acid, any compatible mixture of acids such as those givenas examples herein, and any other acid and mixture thereof that areregarded as equivalents or acceptable substitutes in light of theordinary level of skill in this technology.

When the compound of Formula (I) or Formula (II) is an acid, such as acarboxylic acid or sulfonic acid, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method, for example,treatment of the free acid with an inorganic or organic base, such as anamine (primary, secondary or tertiary), an alkali metal hydroxide,alkaline earth metal hydroxide, any compatible mixture of bases such asthose given as examples herein, and any other base and mixture thereofthat are regarded as equivalents or acceptable substitutes in light ofthe ordinary level of skill in this technology. Illustrative examples ofsuitable salts include organic salts derived from amino acids, such asN-methyl-D-glucamine, lysine, choline, glycine and arginine, ammonia,carbonates, bicarbonates, primary, secondary, and tertiary amines, andcyclic amines, such as tromethamine, benzylamines, pyrrolidines,piperidine, morpholine, and piperazine, and inorganic salts derived fromsodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,aluminum, and lithium.

The invention also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula (I) and Formula (II), and treatment methodsemploying such pharmaceutically acceptable prodrugs. The term “prodrug”means a precursor of a designated compound that, followingadministration to a subject, yields the compound in vivo via a chemicalor physiological process such as solvolysis or enzymatic cleavage, orunder physiological conditions (e.g., a prodrug on being brought tophysiological pH is converted to the compound of Formula (I) or Formula(II)). A “pharmaceutically acceptable prodrug” is a prodrug that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to the subject. Illustrative procedures for theselection and preparation of suitable prodrug derivatives are described,for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Exemplary prodrugs include compounds having an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I) orFormula (II). Examples of amino acid residues include the twentynaturally occurring amino acids, commonly designated by three lettersymbols, as well as 4-hydroxyproline, hydroxylysine, demosine,isodemosine, 3-methylhistidine, norvalin, beta-alanine,gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithineand methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) orFormula (II) as amides or alkyl esters. Examples of amides include thosederived from ammonia, primary C₁₋₆alkyl amines and secondarydi(C₁₋₆alkyl) amines. Secondary amines include 5- or 6-memberedheterocycloalkyl or heteroaryl ring moieties. Examples of amides includethose that are derived from ammonia, C₁₋₃alkyl primary amines, anddi(C₁₋₂alkyl)amines. Examples of esters of the invention includeC₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, and phenyl(C₁₋₆alkyl) esters.Preferred esters include methyl esters. Prodrugs may also be prepared byderivatizing free hydroxy groups using groups including hemisuccinates,phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, following procedures such as thoseoutlined in Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130.Carbamate derivatives of hydroxy and amino groups may also yieldprodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters ofhydroxy groups may also provide prodrugs. Derivatization of hydroxygroups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acylgroup may be an alkyl ester, optionally substituted with one or moreether, amine, or carboxylic acid functionalities, or where the acylgroup is an amino acid ester as described above, is also useful to yieldprodrugs. Prodrugs of this type may be prepared as described in Robinsonet al., J Med Chem. 1996, 39(1), 10-18. Free amines can also bederivatized as amides, sulfonamides or phosphonamides. All of theseprodrug moieties may incorporate groups including ether, amine, andcarboxylic acid functionalities.

The present invention also relates to pharmaceutically activemetabolites of the compounds of Formula (I) or Formula (II), which mayalso be used in the methods of the invention. A “pharmaceutically activemetabolite” means a pharmacologically active product of metabolism inthe body of a compound of Formula (I) or Formula (II) or salt thereof.Prodrugs and active metabolites of a compound may be determined usingroutine techniques known or available in the art. See, e.g., Bertolini,et al., J Med Chem. 1997, 40, 2011-2016; Shan, et al., J Pharm Sci.1997, 86 (7), 765-767; Bagshawe, Drug Dev Res. 1995, 34, 220-230; Bodor,Adv Drug Res. 1984, 13, 224-331; Bundgaard, Design of Prodrugs (ElsevierPress, 1985); and Larsen, Design and Application of Prodrugs, DrugDesign and Development (Krogsgaard-Larsen, et al., eds., HarwoodAcademic Publishers, 1991).

The compounds of Formula (I) or Formula (II) and their pharmaceuticallyacceptable salts, pharmaceutically acceptable prodrugs, andpharmaceutically active metabolites of the present invention are usefulas modulators of the orexin receptor in the methods of the invention. Assuch modulators, the compounds may act as antagonists, agonists, orinverse agonists. The term “modulators” include both inhibitors andactivators, where “inhibitors” refer to compounds that decrease,prevent, inactivate, desensitize or down-regulate orexin receptorexpression or activity, and “activators” are compounds that increase,activate, facilitate, sensitize, or up-regulate orexin receptorexpression or activity.

The term “treat” or “treating” as used herein is intended to refer toadministration of an active agent or composition of the invention to asubject for the purpose of effecting a therapeutic benefit throughmodulation of orexin receptor activity. Treating includes reversing,ameliorating, alleviating, inhibiting the progress of, or lessening theseverity of a disease, disorder, or condition, or one or more symptomsof such disease, disorder or condition mediated through modulation oforexin receptor activity. The term “subject” refers to a mammalianpatient in need of such treatment, such as a human.

Accordingly, the invention relates to methods of using the compoundsdescribed herein to treat subjects diagnosed with or suffering from adisease, disorder, or condition mediated by orexin receptor activity,such as: disorders of the sleep-wake cycle, metabolic disorders,neurological disorders and other disorders (e.g., feeding, drinking,arousal, stress, addiction, metabolism and reproduction). Symptoms ordisease states are intended to be included within the scope of “medicalconditions, disorders, or diseases.”

Sleep disorders include, but are not limited to, sleep-wake transitiondisorders, insomnia, restless legs syndrome, jet-lag, disturbed sleep,and sleep disorders secondary to neurological disorders (e.g., manias,depressions, manic depression, schizophrenia, and pain syndromes (e.g.,fibromyalgia, neuropathic).

Metabolic disorders include, but are not limited to, overweight orobesity and conditions related to overweight or obesity, such as insulinresistance, type II diabetes, hyperlipidemia, gallstones, angina,hypertension, breathlessness, tachycardia, infertility, sleep apnea,back and joint pain, varicose veins and osteoarthritis.

Neurological disorders include, but are not limited to, Parkinson'sdisease, Alzheimer's disease, Tourette's Syndrome, catatonia, anxiety,delirium and dementias.

Other disorders include, but are not limited to, ulcers, irritable bowelsyndrome, diarrhea and gastroesophageal reflux.

In treatment methods according to the invention, an effective amount ofa pharmaceutical agent according to the invention is administered to asubject suffering from or diagnosed as having such a disease, disorder,or condition. An “effective amount” means an amount or dose sufficientto generally bring about the desired therapeutic or prophylactic benefitin patients in need of such treatment for the designated disease,disorder, or condition. Effective amounts or doses of the compounds ofthe present invention may be ascertained by routine methods such asmodeling, dose escalation studies or clinical trials, and by taking intoconsideration routine factors, e.g., the mode or route of administrationor drug delivery, the pharmacokinetics of the compound, the severity andcourse of the disease, disorder, or condition, the subject's previous orongoing therapy, the subject's health status and response to drugs, andthe judgment of the treating physician. An example of a dose is in therange of from about 0.001 to about 200 mg of compound per kg ofsubject's body weight per day, preferably about 0.05 to 100 mg/kg/day,or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g.,BID, TID, QID). For a 70-kg human, an illustrative range for a suitabledosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about2.5 g/day.

Once improvement of the patient's disease, disorder, or condition hasoccurred, the dose may be adjusted for preventative or maintenancetreatment. For example, the dosage or the frequency of administration,or both, may be reduced as a function of the symptoms, to a level atwhich the desired therapeutic or prophylactic effect is maintained. Ofcourse, if symptoms have been alleviated to an appropriate level,treatment may cease. Patients may, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In addition, the active agents of the invention may be used incombination with additional active ingredients in the treatment of theabove conditions. The additional active ingredients may becoadministered separately with an active agent of compounds of Formulas(I) and (II) or included with such an agent in a pharmaceuticalcomposition according to the invention. In an exemplary embodiment,additional active ingredients are those that are known or discovered tobe effective in the treatment of conditions, disorders, or diseasesmediated by orexin activity, such as another orexin modulator or acompound active against another target associated with the particularcondition, disorder, or disease. The combination may serve to increaseefficacy (e.g., by including in the combination a compound potentiatingthe potency or effectiveness of an active agent according to theinvention), decrease one or more side effects, or decrease the requireddose of the active agent according to the invention.

The active agents of the invention are used, alone or in combinationwith one or more additional active ingredients, to formulatepharmaceutical compositions of the invention. A pharmaceuticalcomposition of the invention comprises: (a) an effective amount of atleast one active agent in accordance with the invention, and (b) apharmaceutically acceptable excipient.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of an agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the active agents may be prepared using suitablepharmaceutical excipients and compounding techniques known or thatbecome available to those skilled in the art. The compositions may beadministered in the inventive methods by a suitable route of delivery,e.g., oral, parenteral, rectal, topical, or ocular routes, or byinhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, the compositions areformulated for intravenous infusion, topical administration, or oraladministration.

For oral administration, the compounds of the invention can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. To prepare the oral compositions, the compounds may beformulated to yield a dosage of, e.g., from about 0.05 to about 100mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about0.1 to about 10 mg/kg daily. For example, a total daily dosage of about5 mg to 5 g daily may be accomplished by dosing once, twice, three, orfour times per day.

Oral tablets may include a compound according to the invention mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservative agents.Suitable inert fillers include sodium and calcium carbonate, sodium andcalcium phosphate, lactose, starch, sugar, glucose, methyl cellulose,magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquidoral excipients include ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are suitable disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid or talc. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinaltract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, compounds of the invention may bemixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsulesmay be prepared by mixing the compound of the invention with water, anoil such as peanut oil or olive oil, liquid paraffin, a mixture of monoand di-glycerides of short chain fatty acids, polyethylene glycol 400,or propylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The active agents of this invention may also be administered by non-oralroutes. For example, the compositions may be formulated for rectaladministration as a suppository. For parenteral use, includingintravenous, intramuscular, intraperitoneal, or subcutaneous routes, thecompounds of the invention may be provided in sterile aqueous solutionsor suspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms will be presented inunit-dose form such as ampules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses may rangefrom about 1 to 1000 μg/kg/minute of compound, admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days.

For topical administration, the compounds may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the compounds of theinvention may utilize a patch formulation to affect transdermaldelivery.

Compounds of the invention may alternatively be administered in methodsof this invention by inhalation, via the nasal or oral routes, e.g., ina spray formulation also containing a suitable carrier.

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables are asdefined above in reference to Formula (I). Reactions may be performedbetween the melting point and the reflux temperature of the solvent, andpreferably between 0° C. and the reflux temperature of the solvent.Reactions may be heated employing conventional heating or microwaveheating. Reactions may also be conducted in sealed pressure vesselsabove the normal reflux temperature of the solvent.

Abbreviations and acronyms used herein include the following:

Term Acronym High-performance liquid chromatography HPLC Thin layerchromatography TLC Diisopropylethylamine DIPEA Tetrahydrofuran THFtert-Butylcarbamoyl BOC Carboxybenzyl CBz Dichloromethane DCMTrifluoroacetic acid TFA Acetic Acid HOAc N,N-Dimethylformamide DMFMethanol MeOH Isopropanol IPA Ethanol EtOH Acetonitrile ACN EthylAcetate EtOAc, or EA Triethylamine TEA2-(1H-9-Azobenzotriazole-1-yl)-1,1,3,3- HATU tetramethylaminiumhexafluorophosphate 1-Hydroxy-7-azabenzotriazole HOAT Methyl TertiaryButyl Ether MTBE N-(3-Dimethylaminopropyl)-N- EDCI ethylcarbodiimide[1,1′- PdCl₂(dppf)-dcm adductBis(diphenylphosphino)ferrocene]palladium(II) Dichloride DichloromethaneAdduct

Intermediate compounds of formulae (VIa) and (VIb) are readily preparedas outlined in Scheme A from a commercially available or syntheticallyaccessible compound of formula (IV). Compounds of formula (VIa) areobtained by reacting a compound of formula (IV), where R^(a2) is —H,halo, —C₁₋₄alkyl, —C₁₋₄alkoxy, —NO₂, —NHCOCH₃, or two R^(a2) members maycome together to form a 6-membered aryl ring, where X is C or N (withthe proviso that only one X member can be N), with commerciallyavailable HET compounds of formula (V), where HET is a 5-6 memberedheteroaryl ring containing one to three nitrogen members, in thepresence of copper(I)iodide, Cs₂CO₃ andN,N′-dimethylcyclohexane-1,2-diamine; in a solvent such as DMF ordioxane, at temperatures ranging from 60° C. to 100° C. (usingconventional or microwave heating). One skilled in the art willrecognize that 1,2,3-triazole can exist in two tautomeric forms definedas 2H-[1,2,3]triazole and 1H-[1,2,3]triazole thus accounting for theformation of two regioisomers.

Alternatively, compounds of formula (VIb) are prepared by the reactionof halobenzonitrile compounds of formula (VII) with HET, where HET is a5-membered heteroaryl ring selected from the group consisting oftriazole or pyrazole, in a solvent such as DMF and the like, in thepresence of an inorganic base such as K₂CO₃ and the like, attemperatures ranging from 100° C. to 130° C. Subsequent hydrolysis ofthe nitrile using a base such as aqueous NaOH and the like, in a solventsuch as methanol provides compounds of formula (VIb).

Compounds of formula (VIb) are also prepared by the reaction ofhalobenzonitrile compounds of formula (VII) with HET-Sn(alkyl)₃, whereHET-Sn(alkyl)₃ is a commercially available or synthetically accessibletrialkyltinheteroaryl compound, in a solvent such as DME, in thepresence of a palladium catalyst such as Pd(PPh₃)₄, in the presence orabsence of a catalytic amount of copper iodide, at temperatures rangingfrom 100° C. to 160° C., using conventional or microwave heating.Subsequent hydrolysis of the nitrile using a base such as aqueous NaOHand the like, in a solvent such as methanol provides compounds offormula (VIb).

Compounds of formula (VIb) are also prepared by the reaction ofhalobenzonitrile compounds of formula (VII) with HET-boronic acid, whereHET-boronic acid is a commercially available or synthetically accessibleheteroarylboronic acid, in a solvent such as DME, in the presence of abase such as NaHCO₃, a palladium catalyst such as Pd(PPh₃)₄, attemperatures ranging from 80° C. to the reflux temperature of thesolvent. Subsequent hydrolysis using a base such as aqueous NaOH and thelike, in a solvent such as methanol provides compounds of formula (VIb).

Compounds of formula (I), where R^(b2) is —I, are further elaborated tocompounds of formula (I), where R^(b2) is HET, where HET is a 5-6membered heteroaryl ring containing one to three nitrogen atomsoptionally containing one oxygen member. Reaction of compounds offormula (I), where R^(b2) is —I, with HET-Sn(alkyl)₃, whereHET-Sn(alkyl)₃ is a commercially available or synthetically accessibletrialkyltinheteroaryl compound, in a solvent such as DME, in thepresence of a palladium catalyst such as Pd(PPh₃)₄, in the presence orabsence of a catalytic amount of copper iodide, at temperatures rangingfrom 100° C. to 160° C., using conventional or microwave heating,provides compounds of formula (I).

According to Scheme B, compounds of formula (VIc) are obtained fromcompounds of formula (IV), by first converting a commercially availableor synthetically accessible compound of formula (IV), where R^(a2) is—H, halo, —C₁₋₄alkyl, —C₁₋₄alkoxy, —CF₃, or —NO₂, and where X is C or N(with the proviso that only one X may be N) to one of formula (IX) underesterification conditions, for example by treating an alcohol solutionof a compound of formula (IV) with an acid. In a preferred method thecompound of formula (IV) is dissolved in a solvent such as MeOH andtreated with H₂SO₄ to afford a compound of formula (IX). A compound offormula (X) is obtained by reacting a suitable compound of formula (IX)with pinacol borane in the presence of a phosphine and a palladiumcatalyst, in the presence of an amine base, in a solvent such as THF, attemperatures ranging from room temperature to 70° C. In a preferredmethod the phosphine is tri(o-tolyl)phosphine, the palladium catalyst isPd(OAc)₂ and the amine base is triethylamine.

A compound of formula (VIc) is obtained by reacting a compound offormula (X) with a compound R^(b2)—Cl, where R^(b2)—Cl is a suitablecommercially available or synthetically accessible 6-memberedchloro-substituted heteroaryl compound, in the presence of a palladiumcatalyst, a base such as Na₂CO₃, and the like, in a solvent such as2-methyl-tetrahydrofuran (2-methyl-THF), and the like, at temperaturesranging from room temperature to 80° C. In a preferred method thepalladium catalyst is PdCl₂(dppf)-dcm adduct, the base is Na₂CO₃ and thesolvent is 2-methyl-THF. A compound of formula (VIc) is obtained from acompound of formula (XI) via ester hydrolysis. In a preferred method ofhydrolysis, a compound of formula (XI) in methyl-THF is treated withaqueous NaOH to afford a compound of formula (VIc).

According to SCHEME C, substituted heteroaryl compounds R²Cl of formula(XIVa) and (XVIb) are prepared from commercially available orsynthetically accessible compounds of formula (XIIIa) or (XIIIb).Pyrimidols of formula (XIIIa) or formula (XIIIb) are commerciallyavailable or are prepared by reacting substituted alkyl malonates offormula (XII), where R^(e) is halo, with urea in the presence of a basesuch as sodium ethoxide and the like; in a suitable solvent such asethanol, at temperatures between room temperature and the refluxtemperature of the solvent. Chlorination of commercially availablepyrimidinols of formula (XIIIb) or synthetically accessible compounds offormula (XIIIa) using a chlorinating agent such as oxalyl chloride andthe like; in a solvent such as CH₂Cl₂, in the presence of a base such asN,N-dimethylaniline and the like; at temperatures ranging between roomtemperature and the reflux temperature of the solvent provideschloropyrimidines of formula (XIVa) or (XIVb). Additionally,chloropyrimidines of formula (XIVa) or (XIVb) are further elaborated.Chloropyrimidines of formula (XIVa) or (XIVb) are reacted with Grignardreagents (R^(g)MgBr) of formula (XV); in the presence of a catalyticamount of Fe(acac)₃, in a solvent such as Et₂O at 0° C., provides alkylchloropyrimidines of formula (XVIa) or (XVIb).

According to Scheme D, compounds of formula (XX) are obtained fromsynthetically accessible or commercially available2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole by first protecting thesecondary nitrogen of 2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole as acarbamate. In a preferred embodiment the carbamate is thetert-butylcarbamate (boc) which is introduced by treating2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole with di-tert-butyl-dicarbonate,in a solvent such as DCM, affording compound (XVII). Compound (XVIII) isobtained from treating compound (XVII) with hydrogen gas, in thepresence of a catalyst. In a particularly preferred embodiment thecatalyst is Pd on carbon, in a solvent such as MeOH in the presence ofAcOH. A compound of formula (XIX) is obtained by treating compound(XVIII) with a compound of formula R²Cl, where R² is as defined informula (I). Commercially available or synthetically accessibleappropriately heteroaryl compounds of formula R²Cl are reacted withcompound (XVIII) in the presence of a suitably selected tertiary organicor inorganic base such as Cs₂CO₃, Na₂CO₃, TEA, and the like; in asolvent such as DMF, dichloromethane, THF, n-butanol, and the like; at atemperature between room temperature and the reflux temperature of thesolvent, using conventional or microwave heating, to afford compounds offormula (XIX). In a preferred embodiment the base is Cs₂CO₃ and thesolvent is DMF. Removal of the tert-butylcarbamate (boc) in compounds offormula (XIX) is accomplished by using methods known to one skilled inthe art, such as, HCl, TFA, or p-toluenesulfonic acid, in a solvent suchas CH₃OH, dioxane, or CH₂Cl₂. In a preferred embodiment, a compound offormula (XIX) is treated with TFA in DCM or HCl to afford a compound offormula (XX).

Compounds of formula (XX) are also obtained from2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole. Referring to Scheme D,2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole is treated with R²Cl, where R²is as defined in a compound of formula (I). Commercially available orsynthetically accessible suitably substituted heteroaryl compounds offormula R²Cl are reacted with compound2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole in the presence of a tertiaryorganic or inorganic base such as Cs₂CO₃, Na₂CO₃, TEA, and the like; ina solvent such as DMF, dichloromethane, THF, and the like; at atemperature between room temperature and the reflux temperature of thesolvent to afford a compound of formula (XXI). In a preferred embodimentthe base is CS₂CO₃ and the solvent is DMF. A compound of formula (XX) isobtained by treating a compound of formula (XXI) with hydrogen gas, inthe presence of a catalyst, in a solvent such as AcOH. In a preferredembodiment the catalyst is Pd on carbon.

Referring to Scheme E, a compound of formula (I) is obtained from acompound of formula (XIX), (XX), or (XXI) by reacting a compound offormula (XIX), (XX), or (XXI) with a compound of formula R¹CO₂H underamide formation conditions. Compounds of formula R¹CO₂H, where R¹ is asdefined in formula (I), are commercially available, as described, orsynthetically accessible appropriately substituted aryl or heteroarylcarboxylic acids. In a preferred embodiment a compound of formula (XIX),(XX), or (XXI), either as a free base or as an acid salt, is reactedwith a compound of formula R¹CO₂H, in the presence of a dehydratingagent such as HOBt/EDAC, CDI, HATU, HOAT; a suitably selected base suchas DIPEA, TEA, and the like; in an organic solvent or mixture thereof,such as toluene, acetonitrile, ethyl acetate, DMF, THF, methylenechloride, and the like; to afford a compound of formula (XXII), (XXIII)or (I). In a particularly preferred embodiment the dehydrating agent isHATU, and the base is DIPEA.

In an alternative embodiment, a compound of formula R¹CO₂H (as describedabove) may be first converted to a compound of formula R¹COCl, orcompound of formula R¹COCl is a commercially available substituted arylsulfonyl chloride. In a preferred embodiment, a compound of formulaR¹CO₂H is treated with thionyl chloride in a solvent such as toluene toafford a compound of formula R¹COCl. A compound of formula (I) isobtained by treating a compound of formula R¹COCl with a compound offormula (XIX), (XX), or (XXI), a suitably selected tertiary organic basesuch as TEA, and the like, in a solvent such as dichloromethane, THF,and the like, at a temperature between room temperature and the refluxtemperature of the solvent. A compound of formula (II) is obtained bytreating a compound of formula R¹SO₂Cl with a compound of formula (XIX),(XXI), or (XXV), where R⁴ is (5-trifluoromethyl)-pyridin-2-yl,(5-trifluoromethyl)-pyrimidin-2-yl, 4,6-dimethylpyrimidin-2-yl, orquinoxalin-2-yl; a suitably selected tertiary organic base such as TEA,and the like, in a solvent such as dichloromethane, THF, and the like,at a temperature between room temperature and the reflux temperature ofthe solvent.

Referring to Scheme E, one skilled in the art will recognize that thesequence of transformations shown in Schemes D and E may be reorderedsuch that amide bond formation may be the initial reaction to givecompounds of formulae (XXII) and (XXIII). Removal of the N-benzyl groupfrom a compound of formulae (XXII) or removal of the carbamate from acompound of formula (XXIII) followed by the reaction with a compoundR²Cl, where R²Cl is as described above gives a compound of formula (I).

3-Fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid and2-fluoro-6-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid are preparedaccording to SCHEME H. 3-Fluorophthalic anhydride was dissolved in asolvent such as MeOH, at temperatures ranging from room temperature tothe reflux temperature of the solvent, to provide acid-esters (XXVIIa)and (XXIIb). Conversion of the acid to the acid chloride is accomplishedunder standard chlorination conditions. In a preferred method the acidis heated with oxalyl chloride in a solvent such as DCM. Subsequentreaction of the acid chloride with N-hydroxyacetamide in a solvent suchas CH₂Cl₂ provides a mixture of esters (XXVIIIa) and (XXVIIIb). Finally,esters (XXVIIIa) and (XXVIIIb) are converted to a mixture of esters(XXIXa) and (XXIXb) and acids (XXXa) and (XXXb) by treatment with abase, preferably sodium acetate, in the presence of a solvent,preferably t-BuOH.

Alternately, acid (XXXa) is prepared by first converting2-fluoro-6-iodobenzoic acid to the acid chloride by reaction with achlorinating agent such as oxalyl chloride, in a solvent such as DCM,with a catalytic amount of DMF, at a temperature of 0° C. Subsequentreaction of the acid chloride with N-hydroxyacetamide in a solvent suchas CH₂Cl₂ provides (Z)—N′-((2-fluoro-6-iodobenzoyl)oxy)acetimidamide.5-(2-Fluoro-6-iodophenyl)-3-methyl-1,2,4-oxadiazole is prepared byreacting (Z)—N′-((2-fluoro-6-iodobenzoyl)oxy)acetimidamide with sodiumacetate, in a solvent such as tert-butanol, at temperatures ranging from100° C. to 110° C. 3-Fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoicacid (XXXa) is prepared by reacting5-(2-fluoro-6-iodophenyl)-3-methyl-1,2,4-oxadiazole with a grignardreagent such as i-PrMgCl, in a suitable solvent such as THE and thelike, at a temperature of −78° C. Subsequent addition of CO₂ gas, at atemperature of −78° C. provides3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (XXXa).

Deuterated pyrimidine compounds of formula (XXXII) are preparedaccording to Scheme H. Acetylacetone is reacted with an inorganic basesuch as K₂CO₃ in deuterated water, at temperatures ranging from 100° C.to 120° C. to provide 1,1,1,3,3,3,5,5-octadeuteriopentane-2,4-dione.1,1,1,3,3,3,5,5-Octadeuteriopentane-2,4-dione is subsequently reactedwith deuterated urea, in a solvent such as deuterated ethanol, 35% wt.DCl in D₂O, at temperatures ranging from 90° C. to 100° C. to providedeuterated pyrimidinols of formula (XXXI). Chlorination under standardchlorinating conditions provides chlorodeuteratedpyrimidine compounds offormula (XXXII).

Compounds of formula (I) may be converted to their corresponding saltsusing methods known to those skilled in the art. For example, amines offormula (I) may be treated with trifluoroacetic acid (TFA), HCl, maleicacid, or citric acid in a solvent such as diethyl ether (Et₂O), CH₂Cl₂,tetrahydrofuran (THF), or methanol (MeOH) to provide the correspondingsalt forms. In a particularly preferred embodiment the acid is HCl andthe solvent is isopropanol.

Compounds prepared according to the schemes described above may beobtained as single enantiomers, diastereomers, or regioisomers, byenantio-, diastero-, or regiospecific synthesis, or by resolution.Compounds prepared according to the schemes above may alternately beobtained as racemic (1:1) or non-racemic (not 1:1) mixtures or asmixtures of diastereomers or regioisomers. Where racemic and non-racemicmixtures of enantiomers are obtained, single enantiomers may be isolatedusing conventional separation methods known to one skilled in the art,such as chiral chromatography, recrystallization, diastereomeric saltformation, derivatization into diastereomeric adducts,biotransformation, or enzymatic transformation. Where regioisomeric ordiastereomeric mixtures are obtained, single isomers may be separatedusing conventional methods such as chromatography or crystallization.

The following examples are provided to further illustrate the inventionand various preferred embodiments.

EXAMPLES

Chemistry:

In obtaining the compounds described in the examples below and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt) under a nitrogen atmosphere. Where solutions were“dried,” they were generally dried over a drying agent such as Na₂SO₄ orMgSO₄. Where mixtures, solutions, and extracts were “concentrated”, theywere typically concentrated on a rotary evaporator under reducedpressure. Reactions under microwave irradiation conditions were carriedout in a Biotage Initiator or CEM Discover instrument.

Normal-phase flash column chromatography (FCC) was performed on silicagel (SiO₂) using prepackaged cartridges, eluting with the indicatedsolvents. Preparative reverse-phase high performance liquidchromatography (HPLC) was performed on a Gilson HPLC with an Xterra PrepRP₁₈ or an XBridge C18 OBD (5 μm, 30×100 mm, or 50×150 mm) column, and agradient of 10 to 99% acetonitrile/water (20 mM NH₄OH) over 12 to 18min, and a flow rate of 30 mL/min. Mass spectra (MS) were obtained on anAgilent series 1100 MSD using electrospray ionization (ESI) in positivemode unless otherwise indicated. Calculated (calcd.) mass corresponds tothe exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker modelDRX spectrometers. The format of the ¹H NMR data below is: chemicalshift in ppm downfield of the tetramethylsilane reference (multiplicity,coupling constant J in Hz, integration).

Chemical names were generated using ChemDraw Ultra 6.0.2 (CambridgeSoftCorp., Cambridge, Mass.) or ACD/Name Version 9 (Advanced ChemistryDevelopment, Toronto, Ontario, Canada).

Intermediate 1: 5-Fluoro-2-[1,2,3]triazol-2-yl-benzoic Acid

5-Fluoro-2-[1,2,3]triazol-2-yl-benzoic acid. To a solution of5-fluoro-2-iodo-benzoic acid (3.86 g, 14.65 mmol), 2H-[1,2,3]triazole(2.5 g, 36.2 mmol), Cs₂CO₃ (8.62 g, 24.5 mmol),trans-N,N′-dimethyl-cyclohexane-1,2-diamine (0.4 mL), CuI (244 mg) andDMF (13 mL) were added to a microwave ready vessel and heated to 100° C.for 10 min. The mixture was cooled, diluted with water, and extractedwith EtOAc. The aqueous layer was acidified and extracted with EtOAc.The organic layer was dried over Na₂SO₄ and concentrated. Chromatography(DCM to 10% MeOH/1% HOAc/DCM) gave the product as a white powder (2.14g, 71%). ¹H NMR (400 MHz, CD₃OD): 7.91 (s, 2H), 7.76 (dd, J=8.9, 4.8 Hz,1H), 7.59 (dd, J=8.5, 2.9 Hz, 1H), 7.49-7.42 (m, 1H).

Intermediates 2-12 were prepared in a manner analogous to Intermediate1.

Intermediate 2: 2-[1,2,3]Triazol-2-yl-benzoic Acid

The title compound was prepared in a manner analogous to Intermediate 1,substituting 2-iodobenzoic acid for 5-fluoro-2-iodo-benzoic acid. Twoproducts were formed in this reaction, 2-[1,2,3]triazol-2-yl-benzoicacid and 2-[1,2,3]triazol-1-yl-benzoic acid, as a result of thetautomeric forms of 1,2,3-triazole. ¹H NMR (400 MHz, CD₃OD): 7.91 (s,2H), 7.85-7.82 (m, 1H), 7.75 (dd, J=8.1, 1.0 Hz, 1H), 7.69 (td, J=7.7,1.5 Hz, 1H), 7.60-7.55 (m, 1H).

Intermediate 3: 2-[1,2,3]Triazol-1-yl-benzoic Acid

The title compound was isolated from the synthesis of Intermediate 2. ¹HNMR (400 MHz, CD₃OD): 6.70 (d, J=0.9 Hz, 1H), 6.50 (dd, J=7.7, 1.5 Hz,1H), 6.30 (d, J=1.0 Hz, 1H), 6.24-6.18 (m, 1H), 6.17-6.11 (m, 1H), 6.01(dd, J=7.8, 1.0 Hz, 1H).

Intermediate 4: 4-Fluoro-2-[1,2,3]triazol-2-yl-benzoic Acid

The title compound was prepared in a manner analogous to Intermediate 1,substituting for 4-fluoro-2-iodo-benzoic acid for5-fluoro-2-iodo-benzoic acid in Step A. ¹H NMR (400 MHz, CD₃OD): 7.93(s, 2H), 7.88 (dd, J=8.7, 5.9 Hz, 1H), 7.56 (dd, J=9.2, 2.5 Hz, 1H),7.38-7.30 (m, 1H).

Intermediate 5: 3-Fluoro-2-[1,2,3]triazol-2-yl-benzoic Acid

The title compound was prepared in a manner analogous to Intermediate 1,substituting for 3-fluoro-2-iodo-benzoic acid for5-fluoro-2-iodo-benzoic acid in Step A. ¹H NMR (400 MHz, CD₃OD): 7.93(s, 2H), 7.81 (d, J=8.3 Hz, 1H), 7.63-7.58 (m, 1H), 7.29 (td, J=8.9, 0.9Hz, 1H).

Intermediate 6: 4-Chloro-2-[1,2,3]triazol-2-yl-benzoic Acid

The title compound was prepared in a manner analogous to Intermediate 1,substituting 4-chloro-2-iodo-benzoic acid for 5-fluoro-2-iodo-benzoicacid in Step A. ¹H NMR (400 MHz, CD₃OD): 7.93 (s, 2H), 7.84-7.78 (m,2H), 7.59 (dd, J=8.3, 2.1 Hz, 1H).

Intermediate 7: 5-Iodo-2-[1,2,3]triazol-2-yl-benzoic Acid

The title compound was prepared in a manner analogous to Intermediate 1,substituting 2-bromo-5-iodobenzoic acid for 5-fluoro-2-iodo-benzoic acidin Step A. ¹H NMR (400 MHz, CD₃OD): 8.09 (d, J=2.0, 1H), 8.03-7.97 (m,1H), 7.95-7.86 (m, 3H), 7.53 (d, J=8.4, 1H).

Intermediate 8: 5-Methyl-2-[1,2,3]triazol-2-yl-benzoic Acid

The title compound was prepared in a manner analogous to Intermediate 1,substituting for 2-iodo-5-methyl benzoic acid for5-fluoro-2-iodo-benzoic acid in Step A. ¹H NMR (400 MHz, CD₃OD): 7.87 (s2H), 7.66 (d, J=1.3 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H), 7.53-7.46 (m, 1H),2.45 (s, 3H).

Intermediate 9: 5-Chloro-2-[1,2,3]triazol-2-yl-benzoic Acid

The title compound was prepared in a manner analogous to Intermediate 1,substituting 5-chloro-2-iodo-benzoic acid for 5-fluoro-2-iodo-benzoicacid in Step A. ¹H NMR (400 MHz, CD₃OD): 7.91 (s, 2H), 7.82-7.74 (m,2H), 7.71-7.66 (m, 1H).

Intermediate 10: 5-Methoxy-2-[1,2,3]triazol-2-yl-benzoic Acid

The title compound was prepared in a manner analogous to Intermediate 1,substituting for 2-iodo-5-methoxy benzoic acid for5-fluoro-2-iodo-benzoic acid in Step A. ¹H NMR (400 MHz, CD₃OD): 7.81(s, J=6.4, 2H), 7.55 (d, J=8.8, 1H), 7.33 (d, J=2.9, 1H), 7.18 (dd,J=8.8, 2.9, 1H), 3.85 (s, 3H).

Intermediate 11: 2-Methyl-6-[1,2,3]triazol-2-yl-benzoic Acid

The title compound was prepared in a manner analogous to Intermediate 1,substituting for 2-iodo-6-methyl benzoic acid for5-fluoro-2-iodo-benzoic acid in Step A. ¹H NMR (400 MHz, CD₃OD): 7.89(s, 2H), 7.72 (d, J=8.1 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H), 7.36 (d, J=7.7Hz, 1H), 2.46 (s, 3H).

Intermediate 12: 2-Fluoro-6-[1,2,3]triazol-2-yl-benzoic Acid

Method A: The title compound was prepared in a manner analogous toIntermediate 1, substituting 2-fluoro-6-iodo-benzoic acid for5-fluoro-2-iodo-benzoic acid. ¹H NMR (400 MHz, CD₃OD): 7.96 (s, 2H),7.87-7.82 (m, 1H), 7.70 (td, J=8.1, 5.1 Hz, 1H), 7.59 (ddd, J=9.7, 8.4,1.4 Hz, 1H).

Method B: 2-Fluoro-6-[1,2,3]triazol-2-yl-benzoic acid. To a 2 L,3-necked, round-bottomed flask equipped with an overhead mechanicalstirrer, thermocouple probe, heating mantle, reflux condenser, andnitrogen inlet were added 2-fluoro-6-iodobenzoic acid (127.6 g, 480mmol), copper iodide (4.57 g, 24 mmol), and Cs₂CO₃ (312.6 g, 959 mmol).To these solids were added dioxane (640 mL), then water (2.6 mL, 144mmol), then 1H-1,2,3-triazole (55.6 mL, 959 mmol), and finallytrans-1,2-dimethylcyclohexane-1,2-diamine (15.1 mL, 96 mmol). Themixture was then warmed to 60° C. for 30 min, then to 83° C. for 30 min,and then to 100° C. for 3 h. After the 3 h at 100° C., the mixture wascooled and then 1 L of MTBE and 1 L of water were added. After vigorousmixing, the layers were separated and the bottom aqueous layer wasacidified to pH 1.72 with ˜148 mL of concentrated hydrochloric acid. Theaqueous was then extracted twice with EtOAc. The combined organic layerswere dried over Na₂SO₄, filtered, and concentrated to provide a darkoil. The oil was stirred overnight in EtOAc (450 mL) and the resultingprecipitate was removed by filtration. The mother-liquors wereconcentrated to a brown solid (106.21 g, 75 wt % by quantitative HPLC,79.7 g, 80%). ¹H NMR (400 MHz, DMSO-d₆): 8.22-8.13 (bs, 2H), 7.84-7.80(m, 1H), 7.74-7.65 (m, 1H), 7.50-7.41 (m, 1H).

Intermediate 13: 5-Fluoro-2-pyrimidin-2-yl-benzoic Acid

Step A: 5-Fluoro-2-iodo-benzoic acid methyl ester. To a 500 mLround-bottomed flask was added 5-fluoro-2-iodo-benzoic acid (23 g, 86.5mmol) in methanol (230 mL). To the resulting solution was added conc.sulfuric acid (2.3 mL, 43.2 mmol). The reaction mixture was warmed to65° C. and stirred for 15 h. The resulting mixture was concentratedunder reduced pressure to give crude product which was then waspartitioned between EtOAc (250 mL) and a half sat. Na₂CO_(3(aq))solution (250 mL). The layers were thoroughly mixed and then separated.The organic layer was dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to give a yellow oil (23 g, 95%yield). ¹H NMR (400 MHz, CDCl₃): 7.94 (dd, J=8.7, 5.4 Hz, 1H), 7.54 (dd,J=9.0, 3.1 Hz, 1H), 6.93 (m, 1H), 3.94 (s, 3H).

Step B:5-Fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acidmethyl ester. To a 1 L round-bottomed flask equipped with a refluxcondenser, temperature probe, and nitrogen line, was added5-fluoro-2-iodo-benzoic acid methyl ester (23 g, 82 mmol) in anhydrousTHE (250 mL). Anhydrous triethylamine (34 mL, 246.4 mmol) was added andthe resulting mixture was degassed with a nitrogen sparge for 5 minutes.Pinacol borane (17.9 mL, 123.2 mmol) was added and the reaction mixturewas degassed once more for 5 minutes. Lastly, tri(o-tolyl)phosphine(1.25 g, 4.1 mmol) and palladium acetate (461 mg, 2.053 mmol) wereadded. Again, the reaction mixture was degassed with a nitrogen sparge.The mixture was heated to 65° C. and stirred for 1 h. After cooling toroom temperature, the reaction mixture was quenched with half sat.ammonium chloride solution (250 mL), and the resulting layers wereseparated. The aqueous layer was extracted with additional ethyl acetate(250 mL) and the combined organics were dried over magnesium sulfate.After filtration and concentration, the crude product was obtained as ayellow oil (23 g). The crude product was then slurried in 25%EtOAc/hexanes (250 mL). The resulting solids were not desired productand were removed by filtration. The resulting solution was thenconcentrated to a yellow oil (21 g, 75 wt % desired, 16.1 g actualproduct, 70% yield), which was used directly in the next step. By¹H-NMR, the crude product was also found to contain 14 wt % pinacol, 6.5wt % ligand, and 4 wt % des-iodo starting material. ¹H NMR (400 MHz,CDCl₃): 7.61 (dd, J=9.5, 2.5 Hz, 1H), 7.52-7.45 (m, 1H), 7.21 (td,J=8.3, 2.5 Hz, 1H), 3.91 (s, 3H), 1.41 (s, 12H).

Step C: 5-Fluoro-2-pyrimidin-2-yl-benzoic acid methyl ester. To a 250 mLround-bottomed flask, was added5-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acidmethyl ester (5.9 g, 21.06 mmol) in 2-methyl-THF (50 mL). To theresulting solution was added 2-chloropyrimidine (2.9 g, 25.28 mmol),sodium carbonate (6.7 g, 63.19 mmol), and water (17 mL). The mixture wasdegassed for 30 minutes. PdCl₂(dppf)-dcm adduct (CAS #72287-26-4) (0.688g, 0.843 mmol) was added and the reaction mixture was degassed once morefor 30 minutes. The reaction mixture was warmed to 74° C. and stirredovernight. To the resulting solution was added diethyl ether (100 mL)and water (100 mL). The layers were thoroughly mixed then separated. Theaqueous layer was extracted with additional diethyl ether (100 mL). Thecombined organics were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure to a brown crude material (5.85 g,49% desired, 2.87 actual product). The crude product was furtherpurified through recrystallization in 10% EtOAc/hexanes. The mixture waswarmed to 70° C. and cooled slowly to room temperature. Afterfiltration, the desired product was obtained as a brown solid (1.72 gactual product, 35% yield overall after recrystallization.) ¹H NMR (400MHz, CDCl₃): 8.78 (d, J=4.9 Hz, 2H), 8.09 (dd, J=8.7, 5.5 Hz, 1H), 7.39(dd, J=8.6, 2.7 Hz, 1H), 7.30-7.20 (m, 2H), 3.77 (s, 3H).

Step D: 5-Fluoro-2-pyrimidin-2-yl-benzoic acid. To a solution of5-fluoro-2-pyrimidin-2-ylbenzoic acid methyl ester (1.72 g, 7.407 mmol)in 2-methyl-THF (20 mL) was added sodium hydroxide (0.74 g, 18.517 mmol)and water (20 mL). The mixture was heated to 72° C. and stirred for 2 h.The layers were separated and the aqueous layer was extracted withadditional MTBE. A 50% HCl_((aq)) solution was then dripped into theaqueous layer until a pH of 1 was reached. The resulting solid werefiltered to provide the desired product as an off-white solid (1.34 g,83% yield). ¹H NMR (400 MHz, CD₃OD): 8.82 (d, J=5.0 Hz, 2H), 7.89 (dd,J=8.6, 5.4 Hz, 1H), 7.53 (dd, J=9.0, 2.7 Hz, 1H), 7.39 (m, 2H).

Intermediate 14: 2-Fluoro-6-pyrimidin-2-yl-benzoic Acid

Step A: 2-Fluoro-6-iodo-benzoic acid methyl ester. To a 200 mLround-bottomed flask were added 2-fluoro-6-iodo-benzoic acid (7.5 g,28.2 mmol), LiOH·H₂O (1.42 g, 33.8 mmol), and THE (100 mL). Theresulting mixture was warmed to 50° C. and stirred for 2 h. Dimethylsulfate (4.03 mL, 42.3 mmol) was then added and the mixture was warmedto 65° C. After 2 h, the mixture was cooled to room temperature andNH₄Cl_((aq)) (50 mL, 13 wt % solution) was added. The two resultinglayers were thoroughly mixed and then separated. The organic layer wasdried over MgSO₄, filtered, and concentrated under reduced pressure to alight brown oil (7.79 g, 99% yield). ¹H NMR (400 MHz, CDCl₃): 7.68-7.60(m, 1H), 7.15-7.06 (m, 2H), 3.98 (s, 3H).

Step B:2-Fluoro-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acidmethyl ester. To a 500 mL round-bottomed flask were added2-fluoro-6-iodo-benzoic acid methyl ester (7.29, 26.0 mmol) andanhydrous THE (150 mL). This mixture was cooled to 0° C. and i-PrMgCl(13.7 mL, 2 M in THF, 27.3 mmol) was added dropwise. After 10 min,2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.58 mL, 27.3mmol) was added. The mixture was allowed to warm to room temperature,and after 30 min NH₄Cl_((aq)) (150 mL, 13 wt % solution) was added. Thelayers were mixed and then separated, and the aqueous layer wasextracted with 100 mL of MTBE. The combined organic layers were driedover Na₂SO₄, filtered, and concentrated to a final mass of 6.07 g (90%wt %, 75% yield). ¹H NMR (400 MHz, CDCl₃): 7.47-7.38 (m, 2H), 7.17-7.11(m, 1H), 3.92 (s, 3H), 1.36 (s, 12H).

Step C: 2-Fluoro-6-pyrimidin-2-yl-benzoic acid methyl ester. To a 250 mLround-bottomed flask under nitrogen were added2-fluoro-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acidmethyl ester (5.46 g, 19.5 mmol) in 2-methyl-THF (50 mL),2-chloropyrimidine (2.68 g, 23.4 mmol), and sodium carbonate (6.2 g,58.5 mmol) in water (17 mL). PdCl₂(dppf)-dcm adduct (CAS #72287-26-4)(1.27 g, 1.56 mmol) was then added and the reaction mixture was warmedto 74° C. and stirred for 2.5 h. After cooling, the mixture was dilutedwith MTBE (50 mL) and water (80 mL). The layers were thoroughly mixedthen separated. The aqueous layer was extracted with additional MTBE(100 mL). The combined organics were dried over magnesium sulfate,filtered, concentrated and then purified by flash chromatography (0-25%EA/hexanes) to provide the title compound (1.72 g, 72 wt %, 30% yield).¹H NMR (400 MHz, CDCl₃): 8.79 (d, J=4.9 Hz, 2H), 8.15 (d, J=7.9 Hz, 1H),7.51 (td, J=8.1, 5.6 Hz, 1H), 7.28-7.20 (m, 2H), 3.92 (s, 3H).

Step D: 2-Fluoro-6-pyrimidin-2-yl-benzoic acid. To a solution of2-fluoro-6-pyrimidin-2-yl-benzoic acid methyl ester (1.36 g, 5.85 mmol)in 2-methyl-THF (20 mL) was added sodium hydroxide (2 M in water, 9.3mL, 18.6 mmol). The mixture was heated to 72° C. and stirred for 9 h.The layers were separated and the aqueous layer acidified to pH 2 bydropwise addition of 50% HCl_((aq)) (3.1 mL). The resulting solids werestirred for 1 h, filtered, washed with water, MTBE, and heptanes, andthen dried to provide the desired product as a white solid (1.12 g, 88%yield). ¹H NMR (400 MHz, CD₃OD): 8.83 (d, J=4.9 Hz, 2H), 8.03 (dd,J=7.9, 0.8 Hz, 1H), 7.59 (td, J=8.1, 5.6 Hz, 1H), 7.40 (t, J=4.9 Hz,1H), 7.34 (ddd, J=9.4, 8.4, 1.0 Hz, 1H).

Intermediate 15: Hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic Acidtert-butyl Ester

Step A. 5-Benzyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acidtert-butyl ester. To a solution of2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole (5.62 g, 27.8 mmol) in DCM (100mL) was added (Boc)₂O (6.16 g, 28.2 mmol). The reaction mixture wasstirred for 24 hours at 23° C. The solvent was removed in vacuo and theresulting product was used in the next step without furtherpurification. MS (ESI) mass calcd. for C₁₈H₂₆N₂O₂, 302.41. m/z found,303.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.36-7.20 (m, 5H), 3.61-3.46 (m,4H), 3.24 (br s, 2H), 2.85-2.72 (m, 2H), 2.70-2.63 (m, 2H), 2.43-2.30(m, 2H), 1.50-1.42 (s, 9H).

Step B: Hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butylester. 5-Benzyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acidtert-butyl ester (19.85 g, 65.6 mmol), MeOH (200 mL), HOAc (3 mL) and10% Pd/C Degussa type (400 mg) were charged to a Parr shaker vial andshaken for 3 days at 70 psi hydrogen gas. The resulting material wasfiltered through Celite® and concentrated. The crude mixture waspurified by flash column chromatography (FCC), DCM to 10% MeOH/DCMcontaining 1% NH₄OH, to afford the product. MS (ESI) mass calcd. forC₁₁H₂₀N₂O₂, 212.29. m/z found, 213.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):3.60-3.55 (m, 2H), 3.38-3.25 (m, 4H), 2.95-2.86 (m, 4H), 1.47 (s, 9H).

Intermediate 16:(2-Fluoro-6-[1,2,3]triazol-2-yl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone

Method A:

Step A:5-(2-Fluoro-6-[1,2,3]triazol-2-yl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester. In a 3-neck round bottom 100 mL flask was addedtoluene (8.5 mL), aqueous sodium carbonate (1.42 g in 10.7 mL water),and Intermediate 15 (0.905 mg, 4.26 mmol). The biphasic mixture wascooled to 0° C. After cooling to 0° C.,2-fluoro-6-[1,2,3]triazol-2-yl-benzoyl chloride was poured over thestirring biphasic mixture of amine and aqueous sodium carbonate. Anexotherm was observed. The mixture was allowed to warm to roomtemperature. After 1 h, a sample of the organic layer was quenched intomethanol and a small amount of acid chloride was determined to remain(observed as its methyl ester). Additional amine (˜50 mg) was added andthe mixture was stirred overnight at room temperature. At the end ofthis period, the layers were separated and 100 mL of methanol were addedto the organic layer. The organic was concentrated and purified usingflash column chromatography (FCC), gradient of 5-50% of a solution of10% MeOH, 0.1% NH₄OH in DCM/DCM. The desired fractions were combined andconcentrated to provide a white foamy solid (1.327 g, 76.8%). MS (ESI):mass calculated for C₂₀H₂₄FN₅O₃, 401.44, m/z found 346.2 [M+H-56]⁺. ¹HNMR (400 MHz, CDCl₃): 7.91-7.73 (m, 3H), 7.53-7.39 (m, 1H), 7.18-7.06(m, 1H), 4.00-2.76 (m, 10H), 1.52-1.33 (m, 9H).

Step B:(2-Fluoro-6-[1,2,3]triazol-2-yl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone.5-(2-Fluoro-6-[1,2,3]triazol-2-yl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester (1.3 g, 3.21 mmol) was taken up in DCM (6.0 mL)and TFA (3.0 mL) was added. The mixture was allowed to stir at rt for 1hr. Solvent was removed and then taken back up in DCM and basified with1 N aq. NaOH. The layers were separated. The aqueous was extracted 2more time with DCM (and a small amount of MeOH). The organics werecombined, dried (Na₂SO₄), filtered, and concentrated to provide thedesired free base product,(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone,as a viscous/foamy residue that was found to be very hydroscopic (950.6mg, 93.3%). MS (ESI): mass calculated for C₁₅H₁₆FN₅O, 301.32, m/z found302.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.90-7.73 (m, 3H), 7.54-7.42 (m,1H), 7.19-7.10 (m, 1H), 3.85-2.65 (m, 10H).

Method B:

Step A: 2-Fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (0.97 g, 4.71 mmol),hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester(Intermediate 15, 1.0 g, 4.71 mmol), HATU (2.68 g, 7.06 mmol), in DMF(18.8 mL) was added DIEA (2.43 mL, 14.13 mmol). The mixture was stirredat rt for 1 hr. The mixture was diluted with EtOAc and washed withwater. The aqueous layer was extracted with EtOAc, the organic layerswere combined, dried (Na₂SO₄), filtered and concentrated to provide thecrude product. Purification (FCC) (5-50% of a solution 10% MeOH, 0.1%NH₄OH in DCM/EtOAc over 25 minutes, and 50-100% from 25-35 minutes)provided5-(2-fluoro-6-[1,2,3]triazol-2-yl-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester (0.376 g, 19.5%).

Step B:(2-Fluoro-6-[1,2,3]triazol-2-yl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone.The title compound was prepared in a manner analogous to Intermediate16, Method A, Step B.

Intermediate 17:Biphenyl-2-yl-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone

The title compound was prepared in a manner analogous to Intermediate16, Method B, substituting biphenyl-2-carboxylic acid for2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid in Step A.

Intermediate 18:[5-(2-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone

The title compound was prepared in a manner analogous to Intermediate16, Method B, substituting5-(2-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid for2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid in Step A. MS (ESI): masscalculated for C₁₇H₁₈FN₃OS, 331.41, m/z found 332.1 [M+1]⁺. ¹H NMR (400MHz, CDCl₃): 7.54-7.45 (m, 1H), 7.40-7.32 (m, 1H), 7.21-7.10 (m, 2H),3.79-3.70 (m, 1H), 3.61-3.50 (m, 2H), 3.22-3.13 (m, 1H), 3.12-3.05 (m,1H), 3.03-2.94 (m, 1H), 2.85-2.45 (m, 8H).

Intermediate 19:(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(5-methyl-2-[1,2,3]triazol-2-yl-phenyl)-methanone

The title compound was prepared in a manner analogous to Intermediate16, Method B, substituting 5-methyl-2-[1,2,3]triazol-2-yl-benzoic acidfor 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid in Step A. MS (ESI):mass calculated for C₁₇H₁₉N₅O, 297.36, m/z found 298.2 [M+1]⁺. ¹H NMR(400 MHz, CDCl₃): 7.88-7.76 (m, 3H), 7.36-7.29 (m, 1H), 7.22-7.18 (m,1H), 3.81-2.59 (m, 10H), 2.42 (s, 3H).

Intermediate 20:2(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(2-[1,2,3]triazol-2-yl-phenyl)-methanone

The title compound was prepared in a manner analogous to Intermediate16, Method B, substituting 2-[1,2,3]triazol-2-yl-benzoic acid for2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid in Step A. MS (ESI): masscalculated for C₁₅H₁₇N₅O, 283.33, m/z found 284.1 [M+1]⁺. ¹H NMR (400MHz, CDCl₃): 7.99 (d, J=8.2, 1H), 7.55-7.51 (m, 1H), 7.48-7.36 (m, 2H),3.99-2.42 (m, 11H).

Intermediate 21:(5-Fluoro-2-[1,2,3]triazol-2-yl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone

The title compound was prepared in a manner analogous to Intermediate16, Method B, substituting 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid(Intermediate 97) for 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid inStep A. MS (ESI): mass calculated for C₁₅H₁₆FN₅O, 301.32, m/z found302.0 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): 7.96 (dd, J=9.0, 4.8, 1H),7.85-7.74 (m, 2H), 7.25-7.17 (m, 1H), 7.16-7.10 (m, 1H), 3.78-2.48 (m,10H).

Intermediate 22:(4-Fluoro-2-[1,2,3]triazol-2-yl-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone

The title compound was prepared in a manner analogous to Intermediate16, Method B, substituting 4-fluoro-2-[1,2,3]triazol-2-yl-benzoic acidfor 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid in Step A. MS (ESI):mass calculated for C₁₅H₁₆FN₅O, 301.32. m/z found 302.0 [M+1]⁺. ¹H NMR(400 MHz, CDCl₃): 7.90-7.72 (m, 3H), 7.43-7.35 (m, 1H), 7.17-7.08 (m,1H), 3.81-3.62 (m, 2H), 3.39-2.56 (m, 8H).

Intermediate 23:2-(4,6-Dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole

Method A:

Step A:5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester. Hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acidtert-butyl ester (1.20 g, 5.6 mmol), 2-chloro-4,6-dimethyl-pyrimidine(1.03 g, 7.2 mmol), Cs₂CO₃ (2.12 g, 6.5 mmol) and DMF (15 mL) werecombined and heated to 100° C. for 24 hours. The reaction was thenallowed to cool and water and EtOAc were added. The products wereextracted into EtOAc, dried over Na₂SO₄, and concentrated. The resultingcrude mixture was purified by flash column chromatography (EA/hex) togive the title compound (1.27 g, 71%). MS (ESI) mass calcd. forC₁₇H₂₆N₄O₂, 318.42. m/z found, 319.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):6.25 (s, 1H), 3.85-3.75 (m, 2H), 3.69-3.46 (m, 4H), 3.38-3.20 (m, 2H),2.94 (br s, 2H), 2.29 (s, 6H), 1.44 (s, 9H).

Step B: 2-(4,6-Dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole.5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester (0.92 g, 2.9 mmol), DCM (10 mL) and TFA (5 mL)were stirred at 23° C. for 2 h. The mixture was concentrated to removethe volatiles, diluted with EtOAc and 1 N aq. NaOH, and extracted withEtOAc (3×). The organic fractions were dried and concentrated to givethe title compound (0.61 g, 96%) that contained a small amount of DCMand was used as is. MS (ESI) mass calcd. for C₁₂H₁₈N₄, 218.30. m/zfound, 219.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 6.27 (s, 1H), 3.81-3.70(m, 2H), 3.55-3.48 (m, 2H), 3.16-3.07 (m, 2H), 2.94-2.78 (m, 4H), 2.29(s, 6H).

Method B:

Step A:2-Benzyl-5-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole.To a 3 L, 3-necked, round-bottomed flask equipped with mechanicalstirrer, reflux condenser, temperature probe, and nitrogen inlet, wasadded 2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole (109 g, 538.8 mmol) inDMF (1.6 L). To the resulting solution were added2-chloro-4,6-methylpyrimidine (76.8 g, 538.8 mmol) and Cs₂CO₃ (351.1 g,1.08 mol). The heterogeneous mixture was heated to 100° C. and stirredfor 15 h. After cooling to room temperature, the mixture was dilutedwith ethyl acetate (1.5 L) and water (1.5 L). The layers were thoroughlymixed and separated. The aqueous layer was extracted with additionalethyl acetate (1.5 L). The combined organics were dried over sodiumsulfate, filtered, and concentrated under reduced pressure to a brownsolid (160 g, 96% yield). MS (ESI) mass calcd. for C₁₉H₂₄N₄, 308.20. m/zfound 309 [M+H]⁺. ¹H-NMR (500 MHz, CDCl₃): 7.32-7.26 (m, 4H), 7.25-7.20(m, 1H), 6.27 (s, 1H), 3.81-3.73 (m, 2H), 3.58 (s, 2H), 3.54 (dd,J=11.4, 3.5 Hz, 2H), 2.95-2.86 (m, 2H), 2.80-2.68 (m, 2H), 2.47-2.40 (m,2H), 2.35-2.24 (s, 6H).

Step B:2-(4,6-Dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole·HOAc. Toa 4 L high pressure autoclave equipped with mechanical stirring,temperature probe, heating jacket, and gas inlet were added 5% Pd/C(66.9 g, Johnson Matthey 5R338, 56.8% H₂O, 3.45 mol %) and a solution of2-benzyl-5-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole(160 g, 519 mmol) and acetic acid (30 mL, 519 mmol) in ethanol (3.2 L).The mixture was stirred at 50° C. under 50 psi of H₂(g) for 4 h. Thecatalyst was removed and the resulting solution was then concentratedunder reduced pressure to provide the desired product as a white solid(144 g, quantitative yield) as the HOAc salt. MS (ESI): mass calcd. forC₁₂H₁₈N₄, 218.15; m/z found 219 [M+H]⁺. ¹H-NMR (CDCl₃, 400 MHz): 6.30(s, 1H), 3.79-3.59 (m, 4H), 3.39 (m, 2H), 3.09-2.88 (m, 4H), 2.29 (s,6H), 1.93 (s, 3H).

Intermediate 24:[4-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]-dimethyl-amine

Step A: Intermediate 24 was prepared in a manner analogous toIntermediate 23, Method A, substituting(4-chloro-6-methoxy-pyrimidin-2-yl)-dimethyl-amine for2-chloro-4,6-dimethyl-pyrimidine in Step A to afford5-(2-dimethylamino-6-methoxy-pyrimidin-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester.

Step B:[4-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]-dimethyl-amine.A mixture of5-(2-dimethylamino-6-methoxy-pyrimidin-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester (700 mg) and TFA (10 mL) was stirred in dioxane(30 mL) at room temperature for 18 h. Then the acid and solvents wereremoved to yield the crude trifluoro acetic acid salt of the titlecompound (1.3 g). The crude was purified by flash column chromatography(FCC) using 0-10% MeOH (2 M NH₃) and DCM (gradient) to yield pure titlecompound (155 mg, 30.4%). MS (ESI) mass calcd. for C₁₃H₂₁N₅O, 263.34.m/z found 264.1 [M+H]⁺. The intermediate was used without furtherpurification.

Intermediate 25:[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl]-dimethyl-amine

Step A: The title compound was prepared in a manner analogous toIntermediate 23, Method A, substituting(6-chloro-2-trifluoromethyl-pyrimidin-4-yl)-dimethyl-amine for2-chloro-4,6-dimethyl-pyrimidine in Step A to afford5-(6-dimethylamino-2-trifluoromethyl-pyrimidin-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester.

Step B:[6-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl]-dimethyl-amine.A mixture of5-(6-dimethylamino-2-trifluoromethyl-pyrimidin-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylicacid tert-butyl ester (600 mg) and TFA (10.0 mL) was stirred in dioxane(30.0 mL) at room temperature for 18 h. Then the acid and solvents wereremoved to yield the crude trifluoro acetic acid salt of the titlecompound (800 mg, 165%). The crude was purified by flash columnchromatography (FCC) using 0-10% MeOH (2M NH₃) and DCM (gradient) toyield pure title compound (260 mg, 53.5%). MS (ESI) mass calcd. forC₁₃H₁₈F₃N₅, 301.32; m/z found 302.2 [M+H]⁺. The intermediate was used assuch in the subsequent reactions.

Intermediate 26:2-(4-Phenyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Intermediate23, Method A, substituting 2-chloro-4-phenyl-pyrimidine for2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI) mass calcd. forC₂₉H₂₆N₄O, 266.35. m/z found, 267.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):6.78-6.70 (m, 1H), 6.55-6.49 (m, 2H), 5.97-5.82 (m, 3H), 5.60-5.47 (m,1H), 2.30-2.20 (m, 2H), 2.02 (dd, J=11.6, 2.6 Hz, 2H), 1.58 (br s, 2H),1.42 (br s, 2H), 1.23 (br s, 2H).

Intermediate 27:2-(4-Methyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Intermediate23, Method A, substituting 2-chloro-4-methyl-pyrimidine for2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI) mass calcd. forC₁₁H₁₆N₄, 204.28. m/z found, 205.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):8.20-8.12 (m, 1H), 8.16 (d, J=5.0 Hz, 1H), 6.43-6.33 (m, 1H), 6.38 (d,J=5.0 Hz, 1H), 3.81-3.69 (m, 2H), 3.52 (dd, J=11.6, 3.2 Hz, 2H), 3.16(dd, J=11.1, 6.5 Hz, 2H), 2.97-2.77 (m, 5H), 2.33 (s, 3H).

Intermediate 28: 2-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-benzooxazole

The title compound was prepared in a manner analogous to Intermediate23, Method A, substituting 2-chloro-benzooxazole for2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI) mass calcd. forC₁₁H₁₆N₄, 229.28. m/z found, 230.15 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.43-7.33 (m, 1H), 7.29-7.22 (m, 1H), 7.120-7.13 (m, 1H), 7.05-6.98 (m,1H), 3.89-3.77 (m, 2H), 3.55 (dd, J=10.9, 3.2 Hz, 2H), 3.25-3.15 (m,2H), 3.02-2.90 (m, 2H), 2.88-2.79 (m, 2H).

Intermediate 29:2-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-3-methyl-quinoxaline

The title compound was prepared in a manner analogous to Intermediate 23substituting 2-chloro-3-methyl-quinoxaline for2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI) mass calcd. forC₁₅H₁₈N₄, 254.34. m/z found, 255.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.78(dd, J=8.2, 1.1 Hz, 1H), 7.73 (dd, J=8.3, 0.9 Hz, 1H), 7.59-7.54 (m,1H), 7.48-7.43 (m, 1H), 3.78-3.69 (m, 2H), 3.58 (dd, J=11.0, 3.1 Hz,2H), 3.18-3.12 (m, 2H), 2.99-2.90 (m, 2H), 2.81 (dd, J=11.6, 4.0 Hz,2H), 2.75 (s, 3H).

Intermediate 30:2-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-3-trifluoromethyl-quinoxaline

The title compound was prepared in a manner analogous to Intermediate 23substituting 2-chloro-3-trifluoromethyl-quinoxaline for2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI) mass calcd. forC₁₅H₁₅F₃N₄, 308.31. m/z found 309.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):8.00-7.89 (m, 1H), 7.83-7.70 (m, 2H), 7.60-7.52 (m, 1H), 3.81-3.73 (m,2H), 3.61 (dd, J=11.3, 3.0 Hz, 2H), 3.18-3.13 (m, 2H), 2.99-2.92 (m,2H), 2.78 (dd, J=11.6, 4.1 Hz, 2H).

Intermediate 31:2-(6-Methyl-2-trifluoromethyl-pyrimidin-4-yl)-octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Intermediate 23substituting 4-chloro-6-methyl-2-trifluoromethyl-pyrimidine for2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI) mass calcd. forC₁₂H₁₅F₃N₄, 272.27; m/z found, 273.2 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):6.48 (s, 1H), 3.90-3.24 (m, 4H), 3.20-3.10 (m, 2H), 3.00 (br s, 2H),2.82-2.75 (m, 2H), 2.39 (s, 3H).

Intermediate 32:2-(4-Methoxy-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Intermediate 23substituting 2-chloro-4-methoxy-pyrimidine for2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI): mass calculatedfor C₁₁H₁₆N₄O, 220.27, m/z found 221.2 [M+1]⁺. ¹H NMR (400 MHz, CD₃OD):8.00 (d, J=6.0, 1H), 6.12 (d, J=6.0, 1H), 4.23 (s, 1H), 3.94 (s, 3H),3.84-3.75 (m, 2H), 3.70-3.59 (m, 4H), 3.28-3.15 (m, 4H).

Intermediate 33:2-(4-Trifluoromethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Intermediate24, substituting 2-chloro-4-trifluoromethyl-pyrimidine for2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI): mass calculatedfor C₁₁H₁₃F₃N₄, 258.25, m/z found 259.1 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃):8.52 (d, J=4.9, 1H), 6.88-6.83 (m, 1H), 3.94-3.54 (m, 6H), 3.29-3.11 (m,4H).

Intermediate 34:2-(3,6-Dimethyl-pyrazin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Intermediate 23substituting 3-chloro-2,5-dimethyl-pyrazine for2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI): mass calculatedfor C₁₂H₁₈N₄, 218.30, m/z found 219.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃):10.13-9.85 (m, 1H), 7.89 (s, 1H), 3.71-3.40 (m, 6H), 3.17 (s, 4H), 2.54(s, 3H), 2.39 (s, 3H).

Intermediate 35: 2-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-quinoxaline

The title compound was prepared in a manner analogous to Intermediate 23substituting 2-chloro-quinoxaline for 2-chloro-4,6-dimethyl-pyrimidinein Step A. MS (ESI): mass calculated for C₁₄H₁₆N₄, 240.31, m/z found241.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): 8.39-8.34 (m, 1H), 7.91-7.84 (m,1H), 7.72-7.66 (m, 1H), 7.60-7.53 (m, 1H), 7.40-7.32 (m, 1H), 3.95-3.80(m, 2H), 3.65-3.52 (m, 2H), 3.27-3.11 (m, 2H), 3.08-2.94 (m, 2H),2.92-2.82 (m, 2H).

Intermediate 36:[4-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-trifluoromethyl-pyrimidin-2-yl]-dimethyl-amine

The title compound was prepared in a manner analogous to Intermediate 23substituting (4-chloro-6-trifluoromethyl-pyrimidin-2-yl)-dimethyl-aminefor 2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI): masscalculated for C₃₄H₁₈F₃N₅, 301.32, m/z found 302.1 [M+1]⁺. ¹H NMR (400MHz, CDCl₃): 5.92 (s, 1H), 3.91-3.54 (m, 2H), 3.50-3.24 (m, 2H),3.21-3.05 (m, 9H), 2.99-2.75 (m, 4H).

Intermediate 37:(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(2-thiophen-2-yl-phenyl)-methanone

The title compound was prepared in a manner analogous to Intermediate16, Method B, substituting 2-thiophen-2-yl-benzoic acid for2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid in Step A. MS (ESI): masscalculated for C₁₇H₁₈N₂OS, 298.41, m/z found 299.1 [M+1]⁺. ¹H NMR (400MHz, CDCl₃): 7.55-7.50 (m, 1H), 7.48-7.31 (m, 4H), 7.22-7.11 (m, 1H),7.08-7.03 (m, 1H), 4.06-1.63 (m, 10H).

Intermediate 38:(2,4-Dimethoxy-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone

The title compound was prepared in a manner analogous to Intermediate16, Method B, substituting 2,4-dimethoxybenzoic acid for2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid and substituting EDCl forHATU in Step A.

Intermediate 39:2-(4,6-Dimethoxy-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Intermediate 23utilizing 2-chloro-4,6-dimethoxypyrimidine andhexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester asstarting materials.

Intermediate 40:6-Chloro-2-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-benzothiazole

The title compound was prepared in a manner analogous to Intermediate 23utilizing 2,6-dichloro-benzothiazole andhexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester asstarting materials.

Intermediate 41:(2,6-Dimethoxy-phenyl)-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone

The title compound was prepared in a manner analogous to Intermediate16, Method B, substituting 2,6-dimethoxybenzoic acid for2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid in Step A.

Intermediate 42:2-(4,5,6-trimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Intermediate 23substituting 2-chloro-4,5,6-trimethylpyrimidine (Intermediate 56) for2-chloro-4,6-dimethylpyrimidine in Step A. MS (ESI): mass calculated forC₂₄H₂₅FN₆O, 232.17. m/z found 233.1 [M+H]⁺.

Intermediate 43:6-Fluoro-2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)quinazoline

The title compound was prepared in a manner analogous to Intermediate 23substituting 2-chloro-6-fluoroquinazoline for2-chloro-4,6-dimethylpyrimidine in Step A. MS (ESI): mass calculated forC₂₄H₂₅FN₆O, 258.13; m/z found 259.1 [M+H]⁺.

Intermediate 44:6,7-Difluoro-2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)quinoxaline

The title compound was prepared in a manner analogous to Intermediate 23substituting 2-chloro-6,7-difluoroquinoxaline for2-chloro-4,6-dimethylpyrimidine in Step A. MS (ESI): mass calculated forC₂₄H₂₅FN₆O, 276.12; m/z found 277.1 [M+H]⁺.

Intermediate 45:2-(4,6-Dimethoxypyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Intermediate 23substituting 2-chloro-4,6-dimethoxypyrimidine for2-chloro-4,6-dimethylpyrimidine in Step A. MS (ESI): mass calculated forC₁₂H₁₈N₄O₂, 250.14; m/z found 251.2 [M+H]⁺.

Intermediate 46: 2-(5-Nitropyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Intermediate 23substituting 2-chloro-5-nitropyrimidine for2-chloro-4,6-dimethylpyrimidine in Step A. MS (ESI): mass calculated forC₁₀H₁₃NO₂, 235.11; m/z found 236.2 [M+H]⁺.

Intermediate 47: Methyl2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate

The title compound was prepared in a manner analogous to Intermediate 23substituting methyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylatefor 2-chloro-4,6-dimethylpyrimidine in Step A. MS (ESI): mass calculatedfor C₁₃H₁₅F₃N₄O₂, 316.11. m/z found 317.2 [M+H]⁺.

Intermediate 48:(5-(4-Fluorophenyl)-2-methylthiazol-4-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner analogous to Intermediate16, Method B, substituting5-(4-fluorophenyl)-2-methylthiazole-4-carboxylic acid for3-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid in the last step. MS (ESI):mass calculated for C₁₂H₁₈N₄, 218.30, m/z found 219.2 [M+1]⁺

Intermediate 49:2-(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-6-methylpyrimidine-4-carbonitrile

The title compound was prepared in a manner analogous to Intermediate 23substituting methyl 2-chloro-6-methylpyrimidine-4-carbonitrile for2-chloro-4,6-dimethylpyrimidine in Step A. MS (ESI): mass calculated forC₁₂H₁₈N₅, 229.3. m/z found 230.2 [M+H]⁺.

Intermediate 50: 3-Fluoro-2-(pyrimidin-2-yl)benzoic Acid

Step A: 3-Fluoro-2-(pyrimidin-2-yl)benzonitrile.2-Iodo-3-fluorobenzonitrile (2.5 g, 10.3 mmol) and 2-tributylstannanepyrimidine (3.7 g, 10.0 mmol) were combined and dissolved in degassedDME (18 ml) then purged with bubbling N₂ for 5 minutes. The reaction wastreated with Pd(PPh₃)₄ (577 mg, 0.5 mmol) and then purged with bubblingfor 5 minutes in a sealed vessel and then heated in microwave at 160° C.for 90 min. The reaction was cooled and filtered through celite andconcentrated to minimum volume and the ppt the formed was diluted withhexanes (40 ml) and cooled to 0° C. then filtered. The solid purified(FCC) (20-100% EA/hex) to give 3-fluoro-2-(pyrimidin-2-yl)benzonitrile.¹H NMR (400 MHz, CDCl₃): 8.93 (d, J=4.9 Hz, 2H), 8.14 (dd, J=9.6, 2.7Hz, 1H), 7.86 (dd, J=8.6, 5.3 Hz, 1H), 7.36 (t, J=4.9 Hz, 1H), 7.32-7.24(m, 1H).

Step B: 3-Fluoro-2-(pyrimidin-2-yl)benzoic acid.3-Fluoro-2-(pyrimidin-2-yl)benzonitrile (98 mg, 0.5 mmol) was dissolvedin MeOH (3 mL) and 2M NaOH (aq, 1 mL). The reaction was heated at refluxfor 15 h, then cooled to 23° C., acidified with 1N aq. HCl to pH=1 andextracted with EtOAc (2×). The combined organics were washed with brineand dried over sodium sulfate to give the title compound. ¹H NMR (400MHz, DMSO-d₆): 8.89 (d, J=4.9 Hz, 1H), 7.74 (dd, J=7.6, 1.2 Hz, 1H),7.63 (td, J=8.0, 5.5 Hz, 1H), 7.60-7.53 (m, 1H), 7.52 (t, J=4.9 Hz, 1H).

Intermediate 51: 5-Fluoro-2-(1H-pyrazol-5-yl)benzoic Acid

Step A: Methyl 2-bromo-5-fluorobenzoate (1.0 g, 4.2 mmol) and(1H-pyrazol-5-yl)boronic acid (485 mg, 4.6 mmol) were combined anddissolved in degassed DME (15 ml) then treated with NaHCO₃(706 mg, 8.4mmol) in water and the reaction purged with bubbling N₂ for 5 minutes.The reaction was treated with Pd(PPh₃)₄ (243 mg (0.2 mmol) and thenpurged with bubbling for 5 minutes in a sealed vessel and then heated toreflux for 2 h. The reaction mixture was cooled to 23° C., filtered, andsolid rinsed with EtOAc. The organic layers were separated, dried andconcentrated. Purification via FCC (ethyl acetate/hexanes, 0-30%)afforded methyl 5-fluoro-2-(1H-pyrazol-5-yl)benzoate (415 mg, 44%).

Step B: A solution of methyl 5-fluoro-2-(1H-pyrazol-5-yl)benzoate (415mg, 1.9 mmol) in EtOH (10 ml) was treated with 4.0 eq of LiOH andstirred and monitored for two hours until the reaction was complete. Thereaction mixture was then made to pH=5, and then the solutionconcentrated under reduced pressure, during which time a ppt formed. Thesolution was concentrated to minimum volume and cooled in ice, filteredand washed with ice water to give 5-fluoro-2-(1H-pyrazol-5-yl)benzoicacid (172 mg, 44%). ¹H NMR (400 MHz, DMSO-d₆): 13.03 (s, 1H), 7.71 (d,J=2.0 Hz, 1H), 7.67 (dd, J=8.3, 5.6 Hz, 1H), 7.37 (td, J=8.6, 2.9 Hz,2H), 6.44 (d, J=2.2 Hz, 1H).

Intermediate 52: 3-Fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic Acid

Step A: 3-Fluoro-2-(2H-1,2,3-triazol-2-yl)benzonitrile and3-fluoro-2-(1H-1,2,3-triazol-1-yl)benzonitrile. A mixture of2,3-difluorobenzonitrile (4.0 g, 28.8 mmol), 2H-1,2,3-triazole (1.9 g,28.8 mmol) in DMF (85.0 mL) and K₂CO₃ (7.9 g, 57.5 mmol) were heated to125° C. for 1.5 h. After cooling to rt, water was added and the mixtureextracted with EtOAc (2×). The combined organics were washed with brineand dried (Na₂SO₄). Purification via FCC (10-100% EtOAc in hexanes) gavetwo products. 3-Fluoro-2-(2H-1,2,3-triazol-2-yl)benzonitrile (1.6 g,29%), ¹H NMR (CDCl₃): 7.99 (s, J=6.6 Hz, 2H), 7.67-7.63 (m, 1H),7.61-7.53 (m, 2H), 7.26 (s, 6H) and3-fluoro-2-(1H-1,2,3-triazol-1-yl)benzonitrile (2.0 g, 38%) ¹H NMR(CDCl₃): 7.97 (dd, J=4.4, 2.8 Hz, 1H), 7.95 (d, J=1.2 Hz, 1H), 7.70 (tt,J=5.7, 2.8 Hz, 1H), 7.65 (td, J=8.1, 4.9 Hz, 1H), 7.62-7.57 (m, 1H).

Step B: 3-Fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. To3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzonitrile (1.5 g, 8.0 mmol) in MeOH(30 mL) was added 2M aq. NaOH (10 mL). The reaction was heated at refluxfor 15 h, then cooled to rt, acidified with 1 N aq. HCl to pH=1 andextracted with DCM (2×). The combined organics were washed with brineand dried (Na₂SO₄). Purification via Agilent (Reverse-Phase HPLC, basicconditions) gave the title compound (290 mg, 18%). ¹H NMR (CDCl₃): 7.90(s, 2H), 7.89-7.85 (m, 1H), 7.63-7.56 (m, 1H), 7.50-7.44 (m, 1H) and3-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Intermediate 53, 140mg, 8%).

Intermediate 53: 3-Methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic Acid

The title compound was obtained during the synthesis of Intermediate 52,Step B. ¹H NMR (CDCl₃): 7.92-7.83 (m, 2H), 7.66 (dd, J=7.9, 1.3 Hz, 1H),7.61-7.54 (m, 1H), 7.27 (dd, J=8.4, 1.2 Hz, 1H), 3.82 (s, 3H).

Intermediate 54: 4-Methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic Acid

The title compound was prepared in a manner analogous to Intermediate12, substituting 2-bromo-4-methoxybenzoic acid for5-fluoro-2-iodo-benzoic acid in Step A. Upon purification, two fractionswere obtained, one containing pure4-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (¹H NMR (CDCl₃):7.99-7.90 (m, 1H), 7.83 (s, 2H), 7.20 (d, J=2.5 Hz, 1H), 7.03 (dd,J=8.8, 2.6 Hz, 1H), 3.89 (s, J=17.6 Hz, 3H), and the other containing amixture of 4-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid and4-methoxy-2-(1H-1,2,3-triazol-2-yl)benzoic acid.

Intermediate 55: 2-Chloro-5-fluoro-4-methylpyrimidine

To a solution of 2,4-dichloro-5-fluoropyrimidine (1.02 g, 6.08 mmol) inTHF/NMP (38 mL/3 mL) was added Fe(acac)₃ (215 mg, 0.61 mmol) and themixture was cooled to 0° C. 3.0 M methylmagnesium bromide in Et₂O (3.04mL, 9.12 mmol) was added dropwise. After 30 min at 0° C., the reactionwas complete and quenched with saturated aqueous NH₄Cl solution. Et₂Owas added and the layers were separated and the aqueous layer wasfurther extracted with several portions of Et₂O. The combined organicextracts were dried over Na₂SO₄, filtered and concentrated in vacuo.Chromatography (Hexanes to 10% EtOAc/Hexanes) gave the desired productas a waxy white solid (430 mg, 48%). ¹H NMR (400 MHz, CDCl₃): 8.35 (s,1H), 2.55 (d, J=2.5 Hz, 3H).

Intermediate 56: 2-Chloro-4,5,6-trimethylpyrimidine

To 4,5,6-trimethylpyrimidin-2-ol (3.69 g, 26.7 mmol) was added POCl₃(21.7 mL, 26.7 mmol) followed by Et₂NPh (2.17 mL, 13.6 mmol) dropwise.The mixture was heated at reflux for 48 h and then added to icedropwise. The aqueous layer was extracted with EtOAc (2×). Extractionwas difficult due to a large amount of precipitate. The aqueous layer pHwas adjusted to pH 4-5 with 28% NH₄OH and was filtered through Celite®.The aqueous layer was then extracted with DCM and the combined organicextracts dried over Na₂SO₄, filtered and concentrated in vacuo to ayellow solid. Chromatography (FCC) (0 to 30% EtOAc/Hex) afforded2-chloro-4,5,6-trimethylpyrimidine (4.26 g, 100%).

Intermediate 57: 2-Chloro-4,5-dimethylpyrimidine

The title compound was prepared in a manner analogous to Intermediate55, substituting 2,4-dichloro-5-methylpyrimidine for2,4-dichloro-5-fluoropyrimidine. MS (ESI): mass calculated for C₆H₇ClN₂,142.03, m/z found 143.1 [M+1]⁺. ¹H NMR (500 MHz, CDCl₃): 8.32-8.25 (m,1H), 2.52-2.46 (m, 3H), 2.28-2.22 (m, 3H).

Intermediate 58:2-(5-(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydro-pyrrolo[3,4-c]pyrrol-2(1H)-yl)-6-methylpyrimidin-4-yltrifluoromethanesulfonate

To a solution of2-[5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6-methylpyrimidin-4-ol(1.02 g, 2.5 mmol) in THE (12 mL) was added 1.0 M KOtBu in THE (5 mL, 5mmol) followed by N-phenylbis(trifluoromethanesulfonimide) (0.893 g, 2.5mmol). The mixture was stirred at room temperature overnight and thendiluted with 2 M aq. K₂CO₃ solution and the layers separated. Theaqueous layer was extracted with DCM and the combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reducedpressure. Chromatography (FCC, Hexanes to 100% EtOAc) afforded thedesired product (1.07 g, 79%) plus a small amount of2-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(4-methoxy-6-methylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole(55 mg, 5%) due to residual MeOH in the pyrimidine starting material. MS(ESI): mass calculated for C₂₁H₁₉F₄N₇O₄S, 541.12, m/z found 542.1[M+1]⁺.

Intermediate 59: tert-Butyl5-{[2-(4H-1,2,4-triazol-3-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

To a solution of Intermediate 15 (1.0 g, 4.73 mmol) in DCM (24 mL) wasadded 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid (895 mg, 4.73 mmol)followed by EDCl (1.36 g, 7.09 mmol), HOBt (959 mg, 7.09 mmol) and TEA(1.97 mL, 14.19 mmol). The mixture was stirred for 14 h at roomtemperature and then washed 2× with saturated aqueous NH₄Cl solution.The organic layer was dried over Na₂SO₄, filtered and concentrated invacuo. Chromatography (DCM to 8% 2M NH₃ in MeOH/DCM) afforded thedesired product as a pale yellow foam (1.36 g, 75%). MS (ESI): masscalculated for C₂₀H₂₅N₅O₃, 383.45, m/z found 384.1 [M+1]⁺. ¹H NMR (500MHz, CDCl₃): 12.62 (s, 1H), 8.19-8.03 (m, 2H), 7.56-7.44 (m, 2H),7.39-7.32 (m, 1H), 3.96-2.72 (m, 10H), 1.53-1.35 (m, 9H).

Intermediate 60: tert-Butyl5-{[2-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

To a heterogeneous mixture of NaH (60% dispersion in mineral oil, 80 mg,2 mmol) in DMF (4 mL) was added Intermediate 59 (641 mg, 1.67 mmol) inDMF (4 mL). 30 min after gas evolution had ceased methyliodide (0.115mL, 1.84 mmol) was added dropwise. The mixture was diluted with H₂O andextracted with EtOAc. The combined organic extracts were dried overNa₂SO₄, filtered and concentrated in vacuo. Chromatography (DCM to 8% 2M NH₃ in MeOH/DCM) afforded two products, tert-butyl5-{[2-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(120 mg, 18%) and tert-butyl5-{[2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(454 mg, 68%) due to the tautomeric nature of the 1,2,4-triazole moiety.MS (ESI): mass calculated for C₂₁H₂₇N₅O₃, 397.21, m/z found 398.2[M+1]⁺. ¹H NMR (500 MHz, CDCl₃): 7.90 (s, 1H), 7.61-7.41 (m, 4H), 3.83(s, 3H), 3.74-3.36 (m, 5H), 3.29-3.12 (m, 3H), 2.88-2.75 (m, 2H), 1.47(s, 9H).

Intermediate 61: tert-Butyl5-{[2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

The title compound was isolated from the synthesis of Intermediate 60.MS (ESI): mass calculated for C₂₁H₂₇N₅O₃, 397.21, m/z found 398.2[M+1]⁺. ¹H NMR (500 MHz, CDCl₃): 8.15-8.07 (m, 1H), 8.03 (s, 1H),7.49-7.40 (m, 2H), 7.37-7.29 (m, 1H), 3.97-3.86 (m, 3H), 3.86-3.27 (m,6H), 3.18-2.73 (m, 4H), 1.54-1.36 (m, 9H).

Intermediate 62: tert-Butyl5-{[2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

The title compound was prepared in a manner analogous to Intermediate 59substituting 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid for2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calculated forC₂₁H₂₆N₄O₄, 398.20; m/z found, 399.2. ¹H NMR (500 MHz, CDCl₃): 8.12 (d,J=7.8 Hz, 1H), 7.63 (td, J=7.6 Hz, 1.2 Hz, 1H), 7.55 (td, J=7.7 Hz, 1.3Hz, 1H), 7.42 (d, J=7.5 Hz, 1H), 3.97-3.86 (m, 1H), 3.76-3.61 (m, 2H),3.56-3.33 (m, 3H), 3.29-3.15 (m, 1H), 3.08-2.93 (m, 2H), 2.90-2.82 (m,1H), 2.45 (s, 3H), 1.51-1.41 (m, 9H).

Intermediate 63: 3-Fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic Acid

Method A:

Step A: 2-Fluoro-6-(methoxycarbonyl)benzoic acid. 3-Fluorophthalicanhydride (377 mg, 2.27 mmol) was dissolved in MeOH (6 mL) and heated toreflux for 15 h. The mixture was concentrated in vacuo and the twoproducts (400 mg, 89%), 2-fluoro-6-(methoxycarbonyl)benzoic acid and3-fluoro-2-(methoxycarbonyl)benzoic acid, were taken on to the next stepwithout purification.

Step B: (Z)-Methyl2-((((1-aminoethylidene)amino)oxy)carbonyl)-3-fluorobenzoate. To aheterogeneous mixture of the two acids from step A (400 mg, 2 mmol) at0° C. in DCM (5 mL) was added oxalyl chloride (0.244 mL, 2.32 mmol)followed by DMF (0.05 mL). Gas evolution commenced immediately and after5 min the ice bath was removed. When gas evolution had ceased and themixture was homogeneous an aliquot was removed and quenched with MeOH.Formation of the methyl ester was confirmed by HPLC and the mixture wasconcentrated in vacuo. The viscous liquid was dissolved in fresh DCM (5mL) and treated with solid N-hydroxyacetamidine (165 mg, 2.22 mmol) inseveral portions followed by TEA (0.351 mL, 2.52 mmol). After stirringfor 14 h at ambient temperature the mixture was concentrated in vacuo.Chromatography (Hex to 100% EtOAc/Hex) afforded two products (477 mg,94%), (Z)-methyl2-((((1-aminoethylidene)amino)oxy)carbonyl)-3-fluorobenzoate and(Z)-methyl 2-((((1-aminoethylidene)amino)oxy)carbonyl)-6-fluorobenzoate,which were taken on to the next step as a mixture. MS (ESI) masscalculated for C₁₁H₁₁FN₂O₄, 254.07. m/z found, 255.0.

Step C: 3-Fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid. To themixture of products from Step B (477 mg, 1.88 mmol) in t-BuOH (9 mL) wasadded NaOAc (156 mg, 1.88 mmol). The mixture was heated at 90° C. for 50h and then concentrated in vacuo. This resulted in four products. Theresidue was dissolved in 1 M aq. K₂CO₃ and extracted with DCM to isolatemethyl 2-fluoro-6-(3-methyl-1,2,4-oxadiazol-5-yl)benzoate and methyl3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoate along with unreacted(Z)-methyl 2-((((1-aminoethylidene)amino)oxy)carbonyl)-3-fluorobenzoate.The aqueous layer was then acidified with concentrated HCl and extractedwith DCM. The combined organic layers from this extraction were driedover Na₂SO₄, filtered and concentrated in vacuo. The acid isomers werepurified on a Prep Agilent system with a XBridge C₁₈ OBD 50×100 mmcolumn eluting with 5 to 99% 0.05% NH₄OH in H₂O/ACN over 17 min toafford the desired product (63 mg, 15%) as a white solid afteracidification with 1 M aq. HCl in Et₂O. MS (ESI) mass calculated forC₁₀H₇FN₂O₃, 222.04. m/z found, 223.0.

Method B:

Step A: (Z)—N′-((2-Fluoro-6-iodobenzoyl)oxy)acetimidamide. To aheterogeneous mixture of 2-fluoro-6-iodobenzoic acid (1.51 g, 5.66 mmol)at 0° C. in DCM (28 mL) was added oxalyl chloride (0.635 mL, 7.36 mmol)followed by DMF (0.15 mL). Gas evolution commenced immediately and after5 min the ice bath was removed. When gas evolution had ceased and themixture was homogeneous an aliquot was removed and quenched with MeOH.Formation of the methyl ester was confirmed by HPLC and the mixture wasconcentrated in vacuo. The viscous liquid was dissolved in fresh DCM (28mL) and treated with solid N-hydroxyacetamidine (503 mg, 6.79 mmol) inseveral portions followed by TEA (1.2 mL, 8.49 mmol) at 0° C. Afterstirring for 14 h at ambient temperature the mixture was washed withsaturated aqueous NaHCO₃ solution. The combined organic extracts weredried over Na₂SO₄, filtered and concentrated in vacuo. Chromatography(Hex to 100% EtOAc/Hex) afforded the desired product as a colorless oil(1.57 g, 86%). MS (ESI) mass calculated for C₉H₈FIN₂O₂, 321.96. m/zfound, 323.0. 1H NMR (500 MHz, CDCl₃): 7.70-7.65 (m, 1H), 7.15-7.11 (m,2H), 4.87 (br s, 2H), 2.06 (s, 3H).

Step B: 5-(2-Fluoro-6-iodophenyl)-3-methyl-1,2,4-oxadiazole. To aheterogeneous mixture of the product of Step A in t-BuOH (24 mL) wasadded NaOAc (603 mg, 7.27 mmol) in H₂O (0.9 mL). The mixture was thenheated to 110° C. for 12 days. The reaction was concentrated in vacuoand then dissolved in toluene. The toluene was then filtered to removeNaOAc and then concentrated in vacuo. Chromatography (Hex to 40%EtOAc/Hex) afforded the desired product as a colorless oil (1.21 g,82%). MS (ESI) mass calculated for C₉H₆FIN₂O, 303.95. m/z found, 304.9.1H NMR (500 MHz, CDCl₃): 7.82-7.77 (m, 1H), 7.29-7.20 (m, 2H), 2.55 (s,3H).

Step C: 3-Fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid. To THE(15 mL) was added 2 M i-PrMgCl in THE (2.2 mL, 4.47 mmol). This mixturewas cooled to −78° C. and the product of Step B (1.09 g, 3.58 mmol) wasadded dropwise in THE (20 mL). The mixture was stirred for 30 min at−78° C. and then CO₂ from a lecture bottle was bubbled into the solutionfor 3 h while allowing the temperature to slowly rise. When thetemperature reached −20° C. the dry ice bath was replaced with an icebath, bubbling of CO₂ was ceased and the mixture was allowed to come toroom temperature overnight. The mixture was quenched by the addition ofH₂O and a small amount of Et₂O. The organic layer was washed 2× with 2Naq. NaOH and the combined aqueous layers were then washed 3× with Et₂O.The aqueous layer was then acidified with concentrated HCl and extractedwith DCM. The combined organic layers were dried over Na₂SO₄, filteredand concentrated in vacuo to afford the desired product as a white solid(661 mg, 83%). MS (ESI) mass calculated for C₁₀H₇FN₂O₃, 222.04. m/zfound, 223.0. 1H NMR (500 MHz, CDCl₃): 7.96 (d, J=7.8, 1H), 7.72-7.64(m, 1H), 7.50-7.44 (m, 1H), 2.56-2.48 (m, 3H).

Intermediate 64: 2-Fluoro-6-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic Acid

The title compound was isolated from the synthesis of Intermediate 63,Method A. MS (ESI) mass calculated for C₁₀H₇FN₂O₃, 222.04. m/z found,223.0. ¹H NMR (500 MHz, CDCl₃): 7.89 (d, J=7.7, 1H), 7.65-7.59 (m, 1H),7.44-7.38 (m, 1H), 2.50 (s, 3H).

Intermediate 65: 2,5-Dichloro-4-methylpyrimidine

The title compound was prepared in a manner analogous to Intermediate55, substituting 2,4,5-trichloropyrimidine for2,4-dichloro-5-fluoropyrimidine. ¹H NMR (500 MHz, CDCl₃): 8.47 (s, 1H),2.61 (s, 3H).

Intermediate 66: 2,5-Dichloro-4,6-dimethylpyrimidine

To 5-chloro-4,6-dimethylpyrimidin-2-ol (992 mg, 6.26 mmol) was addedPOCl₃ (2.22 mL, 23.77 mmol) followed by Et₂NPh (0.75 mL, 4.69 mmol)dropwise. The mixture was heated at 125° C. for 2 h. At approximately 2h the reaction became homogeneous and was checked by HPLC and it showedall starting material had been consumed. The mixture was allowed to coolto room temperature and was then added dropwise to ice. After the icehad melted there was a white solid in a pink liquid. The aqueous layerwas extracted with DCM and the combined organic layers were dried overNa₂SO₄, filtered and concentrated in vacuo. Chromatography (Hex to 10%EtOAc/Hex) afforded the desired product as a white solid (915 mg, 83%).¹H NMR (500 MHz, CDCl₃): 2.57 (s, 6H).

Intermediate 67: 2-Chloro-5-ethyl-4,6-dimethylpyrimidine

The title compound was prepared in a manner analogous to Intermediate56, substituting 5-ethyl-4,6-dimethylpyrimidin-2-ol for4,5,6-trimethylpyrimidin-2-ol. MS (ESI): mass calculated for C₈H₁₁ClN₂,170.06, m/z found 171.1 [M+1]⁺. ¹H NMR (500 MHz, CDCl₃): 2.65 (q, J=7.6Hz, 2H), 2.50 (s, 6H), 1.15 (t, J=7.6 Hz, 3H).

Intermediate 68:(3-(2H-1,2,3-Triazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

Step A: tert-Butyl5-(3-(2H-1,2,3-triazol-2-yl)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.tert-Butyl5-(3-(2H-1,2,3-triazol-2-yl)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylatewas prepared in a manner analogous to Intermediate 59 substituting3-[1,2,3]triazol-2-yl-pyridine-2-carboxylic acid (Intermediate 72) for2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calculated forC₁₉H₂₄N₆O₃, 384.19. m/z found, 385.1.

Step B:(3-(2H-1,2,3-Triazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone.tert-Butyl5-(3-(2H-1,2,3-triazol-2-yl)picolinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(491 mg, 1.28 mmol) in DCM (6 mL) was added TFA (3 mL). After stirringfor 2 h at room temperature the reaction was complete and concentratedin vacuo. The TFA salt was purified on a Prep Agilent system with aXBridge C₁₈ OBD 50×100 mm column eluting with 5 to 99% 0.05% NH₄OH inH₂O/ACN over 17 min to afford(3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanoneas a white solid (306 mg, 84%). MS (ESI) mass calculated for C₁₄H₁₆N₆O,284.14. m/z found, 285.0.

Intermediate 69: 2-Chloro-5-fluoro-4,6-dimethylpyrimidine

Step A: 5-Fluoropyrimidine-2,4,6-triol. To a heterogeneous mixture ofurea (641 mg, 10.67 mmol) and diethylfluoromalonate (1.96 g, 10.67 mmol)in EtOH (11 mL) was added 2.68 M NaOEt in EtOH (7.96 mL, 21.34 mmol).The mixture was heated at reflux for 60 h and then allowed to cool toroom temperature. The mixture was filtered and the cake was thendissolved in warm water and the resulting solution was acidified withconcentrated HCl to pH 2. The mixture was allowed to cool to roomtemperature and then cooled in an ice bath before filtering. The cakewas washed with water and dried to afford 5-fluoropyrimidine-2,4,6-triolas a slightly off white solid (1.45 g, 93%).

Step B: 2,4,6-Trichloro-5-fluoropyrimidine. To POCl₃ (4.49 mL, 48.15mmol) was added 5-fluoropyrimidine-2,4,6-triol (1.41 g, 9.63 mmol) inseveral portions. There was a 2° C. increase in temperature. TheN,N-dimethylaniline (1.23 mL, 9.73 mmol) was then added dropwise and themixture heated at 110° C. for 24 h. The reaction mixture was allowed tocool only briefly and then was quenched by dropwise addition onto ice.When the ice was melted the aqueous layer was extracted several timeswith Et₂O. The combined organic extracts were dried over Na₂SO₄,filtered and concentrated in vacuo to a yellow solid after storing inthe refrigerator overnight. This material was not purified further, buttaken on to the next step without further purification.

Step C: 2-Chloro-5-fluoro-4,6-dimethylpyrimidine was prepared in amanner analogous to Intermediate 55, substituting2,4,6-trichloro-5-fluoropyrimidine for 2,4-dichloro-5-fluoropyrimidine.¹H NMR (500 MHz, CDCl₃): 2.50 (d, J=2.7 Hz, 6H).

Intermediate 70: 6-Methyl-2-[1,2,3]triazol-2-yl-nicotinic Acid

6-Methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. To a 100 ml round bottomflask containing 2-chloro-6-methylnicotinic acid (3 g, 17.4 mmol),copper iodide (0.16 g, 0.5 mol %), and cesium carbonate (11.4 g, 35mmol) was added a mixture of dioxane (20 mL) and H₂O (0.1 ml, 5.25mmol). Next triazole (2.03 mL, 35 mmol) and finally(R,R)—(−)—N,N′-dimethyl-1,2-cyclohexanediamine ligand (0.56 mL, 3.5mmol) were added. The resulting clumpy yellow slurry was stirred untilevenly dispersed. Upon heating to 100° C. the reaction mixture changedfrom a yellow slurry to pale green. As heating progressed the slurrybecame less thick and was stirred more easily. The light green slurrywas stirred for 4 hr at 100° C. and left to stir at room temp overnight.At this point the reaction mixture appeared as a cobalt blue slurrywhich was then diluted with 20 mL ether and 20 mL H₂O. The resultingsolution was thoroughly stirred and transferred to a separatory funnelthen the RBF was subsequently rinsed with 20 mL ether and H₂O each. Theaqueous layer was separated from the organic layer and acidified to pH 1with 6 mL conc. HCl. The now brown/lime green aqueous layer wasextracted twice with EtOAc. The bright yellow organic layers werecombined and dried with Na₂SO₄ and then conc. into a yellow powder underreduced pressure. To the yellow powder was added EtOAc to form a yellowslurry. The solids were filtered off and washed with EtOAc to give avery pale yellow powder, which was found by ¹H NMR to be theIntermediate 71 (25% yield). The filtrate was conc. into a yellow solidand purified (FCC, 0-5% MeOH in DCM w/0.5% AcOH) to give the titleproduct in a 20% yield. MS (ESI): mass calculated for C₉H₈N₄O₂, 204.18.m/z found 205.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.21-8.18 (m, 1H), 7.98(s, 2H), 7.51 (d, J=7.9 Hz, 1H), 2.64 (s, 3H).

Intermediate 71: 6-Methyl-2-[1,2,3]triazol-1-yl-nicotinic Acid

The title compound was isolated as a byproduct from the procedure usedto prepare Intermediate 70 with a 25% yield. MS (ESI): mass calculatedfor C₉H₈N₄O₂, 204.18. m/z found 205.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):8.48 (d, J=1.1 Hz, 1H), 8.25 (dd, J=7.9, 3.8 Hz, 1H), 7.88 (d, J=1.1 Hz,1H), 7.54 (d, J=7.9 Hz, 1H), 2.64 (s, 3H).

Intermediate 72: 3-[1,2,3]Triazol-2-yl-pyridine-2-carboxylic Acid

The title compound was prepared in a manner analogous to Intermediate 70substituting 3-bromo-2-pyridinecarboxylic acid for2-chloro-6-methylnicotinic acid. MS (ESI): mass calculated for C₈H₆N₄O₂,190.10. m/z found 191.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.77 (d, J=4.3Hz, 1H), 8.26 (dt, J=6.5, 3.3 Hz, 1H), 7.88 (s, 2H), 7.65 (dd, J=8.2,4.7 Hz, 1H).

Intermediate 73: 1-[1,2,3]Triazol-2-yl-naphthalene-2-carboxylic Acid

The title compound was prepared in a manner analogous to Intermediate 70substituting 1-bromo-2-napthoic acid for 2-chloro-6-methylnicotinicacid. The title compound was obtained (484 mg, 50%). MS (ESI): masscalculated for C₁₃H₉N₃O₂, 239.23. m/z found 240.3 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): 8.19 (d, J=8.7 Hz, 1H), 8.09-8.03 (m, 4H), 7.70-7.66 (m,1H), 7.58 (ddd, J=8.2, 6.9, 1.2 Hz, 1H), 7.25 (d, J=8.6 Hz, 1H).

Intermediate 74: 1-[1,2,3]Triazol-1-yl-naphthalene-2-carboxylic Acid

The title compound was isolated as a byproduct from the preparation ofIntermediate 73 (25% yield). MS (ESI): mass calculated for C₁₃H₉N₃O₂,239.23; m/z found 240.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.33 (d, J=0.9Hz, 1H), 8.24 (d, J=8.6 Hz, 1H), 8.14-8.07 (m, 2H), 8.01 (d, J=0.9 Hz,1H), 7.71 (t, J=7.6 Hz, 1H), 7.60 (t, J=7.7 Hz, 1H), 7.11 (d, J=8.5 Hz,1H).

Intermediate 75: 8-[1,2,3]Triazol-2-yl-naphthalene-1-carboxylic Acid

The title compound was prepared in a manner analogous to Intermediate 70substituting 8-bromo-2-napthoic acid for 2-chloro-6-methylnicotinicacid. The desired 8-[1,2,3]triazol-2-yl-naphthalene-1-carboxylic acidwas obtained (474 mg, 16%). MS (ESI): mass calculated for C₁H₉N₃O₂,239.20. m/z found 240.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.13 (t, J=9.0Hz, 2H), 7.95-7.91 (m, 3H), 7.82 (dd, J=7.4, 1.0 Hz, 1H), 7.70 (dd,J=9.8, 5.8 Hz, 1H), 7.64-7.59 (m, 1H).

Intermediate 76: 5-[1,2,3]Triazol-2-yl-benzo[1,3]dioxole-4-carboxylicAcid

The title compound was prepared in a manner analogous to Intermediate 70substituting 5-bromobenzo[1,3]dioxole-4-carboxylic acid for2-chloro-6-methylnicotinic acid. MS (ESI): mass calculated forC₁₀H₇N₃O₄, 233.18. m/z found 234.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 7.85(s, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 6.16 (s, 2H).

Intermediate 77: 2,3-Dimethoxy-6-[1,2,3]triazol-2-yl-benzoic Acid

To a 20 ml microwave vial containing 2-bromo-4,5-dimethoxybenzoic acid(3 g, 11.5 mmol), copper iodide (0.04 g, 0.5 mol %), cesium carbonate(7.5 g, 23 mmol), triazole (1.33 mL, 23 mmol) and finally(R,R)—(−)—N,N′-dimethyl-1,2-cyclohexanediamine ligand (0.36 mL, 2.3mmol) was added DMF (12 mL). The resulting clumpy yellow slurry wasstirred until evenly dispersed then heated to 120° C. for 10-20 minusing a microwave. At this point the reaction mixture appeared as a blueslurry which was then diluted with 20 mL ether and 20 mL H₂O. Theresulting solution was thoroughly stirred and transferred to aseparatory funnel then the RBF was subsequently rinsed with 20 mL etherand H₂O each. The aqueous layer was separated from the organic layer andacidified to pH 1 with 6 mL conc. HCl. The now brown/lime green aqueouslayer was extracted twice with EtOAc. The bright yellow organic layerswere combined and dried with Na₂SO₄ and then conc. into a yellow powderunder reduced pressure which was purified by FCC (0-5% MeOH in DCMw/0.5% AcOH) to afford 2,3-dimethoxy-6-[1,2,3]triazol-2-yl-benzoic acid(60%) and 2,3-dimethoxy-6-[1,2,3]triazol-1-yl-benzoic acid (20%). Datafor 2,3-dimethoxy-6-[1,2,3]triazol-2-yl-benzoic acid, MS (ESI): masscalculated for C₁₁H₁₁N₃O₄, 249.23. m/z found 250.3 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): 7.87 (s, 2H), 7.47 (s, 1H), 7.18 (s, 1H), 3.94 (s, 3H),3.91 (s, 3H).

Intermediate 78: 2,3-Dimethoxy-6-[1,2,3]triazol-1-yl-benzoic Acid

The title compound was isolated from the procedure used to prepareIntermediate 77 with a 20% yield. MS (ESI): mass calculated forC₁₁H₁₁N₃O₄, 249.23; m/z found 250.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):8.17 (d, J=1.0 Hz, 1H), 7.82 (d, J=1.0 Hz, 1H), 7.62 (s, 1H), 7.09 (s,1H), 3.95 (s, 3H), 3.91 (s, 3H).

Intermediate 79: 5-Acetylamino-2-[1,2,3]triazol-2-yl-benzoic Acid

The title compound was prepared in a manner analogous to Intermediate 70substituting 5-acetamido-2-bromobenzoic acid for2-bromo-4,5-dimethoxybenzoic acid. MS (ESI): mass calculated forC₁₁H₁₀N₄O₃, 246.22. m/z found 247.3 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD):8.09 (t, J=2.8 Hz, 1H), 7.92-7.86 (m, 3H), 7.66 (dd, J=8.7, 3.3 Hz, 1H),2.17 (dd, J=2.5, 1.3 Hz, 3H).

Intermediate 80: 4-(1H-1,2,3-Triazol-1-yl)nicotinic Acid

The title compound was prepared in a manner analogous to Intermediate 70substituting 4-chloronicotinic acid for 2-chloro-6-methylnicotinic acid.MS (ESI): mass calculated for C₁₁H₁₀N₄O₃, 246.22. m/z found 247.3[M+H]⁺. ¹H NMR (400 MHz, CD₃OD): 8.09 (t, J=2.8 Hz, 1H), 7.92-7.86 (m,3H), 7.66 (dd, J=8.7, 3.3 Hz, 1H), 2.17 (dd, J=2.5, 1.3 Hz, 3H).

Intermediate 81: 3-Methyl-2-(2H-1,2,3-triazol-2-yl)benzonitrile

To a mixture of 2-fluoro-3-methylbenzonitrile (4.0 g, 29.6 mmol) and2H-1,2,3-triazole (2.04 g, 29.6 mmol) in DMF (80 mL) was added potassiumcarbonate (8.26 g, 59.2 mmol). The resulting mixture was heated to 120°C. for 2 h. The mixture was cooled, diluted with water and extractedwith EtOAc. The organic layers were combined, dried over Na₂SO₄,filtered and concentrated. The residue was purified by FCC (SiO₂, ethylacetate/hexanes, gradient 0-50%) to yield the title compound (1.5 g,26%). MS (ESI) mass calcd. for C₁₀H₈N₄, 184.2. m/z found, 185.1 [M+H]+.¹H NMR (500 MHz, CDCl₃): 7.95 (s, 2H), 7.66 (d, J=7.7, 0.7 Hz, 1H), 7.59(d, J=7.8, 0.6 Hz, 1H), 7.50 (dd, J=9.8, 5.7 Hz, 1H), 2.20 (s, 3H).

Intermediate 82: 3-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoic Acid

To a solution of 3-methyl-2-(2H-1,2,3-triazol-2-yl)benzonitrile (1.4 g,7.82 mmol) in MeOH (15 mL) was added a 4N aqueous solution of NaOH (10mL). The resulting mixture was heated to 90° C. After 15 h the reactionmixture was cooled to ambient temperature then diluted with water (50mL). The aqueous layer was acidified to pH2 and extracted with EtOAc (50mL) three times. The organic layers were combined, dried over Na₂SO₄,filtered and concentrated. The residue was purified by FCC (SiO₂,gradient DCM to 10% MeOH/1% HOAc/DCM) to yield the title compound (1.3g, 78%). ¹H NMR (500 MHz, CDCl₃): 7.90 (d, J=7.7, Hz, 1H), 7.83 (s, 2H),7.57-7.53 (m, 1H), 7.49 (dd, J=9.7, 5.8 Hz, 1H), 2.10 (s, 3H).

Intermediate 83: 3-Fluoro-2-(1H-pyrazol-5-yl)benzoic Acid

Method A:

Step A: 2-Bromo-3-fluorobenzonitrile (1.0 g, 5.0 mmol) and(1H-pyrazol-5-yl)boronic acid (647 mg, 4.6 mmol) were combined anddissolved in degassed DME (15 mL) then treated with NaHCO₃ (1260 mg, 8.4mmol) in water and the reaction purged with bubbling N₂ for 5 minutes.The reaction was treated with Pd(PPh₃)₄ (288 mg, 0.2 mmol) and thenpurged with bubbling for 5 minutes in a sealed vessel and then heated toreflux for 2 h. The reaction was then cooled to 23° C. filtered and thesolids were rinsed with EtOAc and the layers separated. The organiclayers were combined, dried and concentrated under reduced pressure.Chromatography (0-30% ethyl acetate/hexanes) afforded3-fluoro-2-(1H-pyrazol-5-yl)benzonitrile (178 mg, 19%).

Step B: To 3-fluoro-2-(1H-pyrazol-5-yl)benzonitrile in MeOH (3 mL) wasadded 2M aq. NaOH (1 mL). The reaction was heated at reflux for 15 h,then cooled to rt, acidified with 1N aq. HCl to pH=1 and extracted withEtOAc to give (210 mg, 99%) of 3-fluoro-2-(1H-pyrazol-5-yl)benzoic acidwhich was used crude.

Method B:

The title compound was prepared in a manner analogous to Intermediate51, substituting methyl 2-iodo-3-fluorobenzoate for methyl2-bromo-5-fluorobenzoate in Step A. MS (ESI): mass calculated forC₁₀H₇FN₂O₂, 206.05; m/z found 207.0 [M+1]⁺.

Intermediate 84: 2-(1H-1,2,3-Triazol-1-yl)-6-(trifluoromethyl)nicotinicAcid

The title compound was prepared in a manner analogous to Intermediate13, substituting 2-chloro-6-(trifluoromethyl)nicotinic acid for5-fluoro-2-iodo-benzoic acid in step A, and substituting 1,4-dioxane forMeOH as the solvent, with 0.3 eq of water as an additive. ¹H NMR (400MHz, DMSO-d₆): 8.64 (s, 1H), 8.37 (d, J=7.6 Hz, 1H), 8.11 (d, J=7.8 Hz,1H), 7.93 (s, 1H).

Intermediate 85: 5-Fluoro-2-(1H-pyrazol-5-yl)benzoic Acid

Step A: Methyl-2-fluoro-bromobenzoate (1.0 gram, 4.2 mmol) and(1H-pyrazol-5-yl)boronic acid (485 mg, 4.6 mmol) were combined anddissolved in degassed DME (15 mL) then treated with NaHCO₃ (706 mg, 8.4mmol) in water and the reaction purged with bubbling N₂ for 5 minutes.The reaction was treated with Pd(PPh₃)₄ (243 mg (0.2 mmol) and thenpurged with bubbling for 5 minutes in a sealed vessel and then heated toreflux for 2 h. The reaction mixture was cooled to 23° C., filtered, andthe solid was rinsed with EtOAc and the layers separated. The organiclayers were combined, dried and concentrated. Chromatography (ethylacetate/hexanes, 0-30%) gave methyl 5-fluoro-2-(1H-pyrazol-5-yl)benzoate(415 mg, 44%).

Step B: A solution of methyl 5-fluoro-2-(1H-pyrazol-5-yl)benzoate (415mg, 1.9 mmol) in EtOH (10 mL) was treated with 4.0 eq of LiOH andstirred and monitored for two hours the reaction was complete. Reactionwas made to pH=5, and then the solution concentrated under reducedpressure during which time a ppt formed. The reactions was thenconcentrated to minimum volume and cooled in ice, then filtered andwashed with ice water to give 5-fluoro-2-(1H-pyrazol-5-yl)benzoic acid(172 mg, 44% yield). ¹H NMR (400 MHz, DMSO-d₆): 13.03 (s, 1H), 7.71 (d,J=2.0 Hz, 1H), 7.67 (dd, J=8.3, 5.6 Hz, 1H), 7.37 (td, J=8.6, 2.9 Hz,2H), 6.44 (d, J=2.2 Hz, 1H).

Intermediate 86: 3-Methyl-2-(1H-1,2,3-triazol-1-yl)benzoic Acid

The title compound was prepared in a manner analogous to Intermediate82, substituting 3-methyl-2-(1H-1,2,3-triazol-1-yl)benzonitrile for3-methyl-2-(2H-1,2,3-triazol-2-yl)benzonitrile. ¹H NMR (500 MHz, CDCl₃):8.17 (s, 1H), 7.94 (s, 1H), 7.69 (d, J=6.8 Hz, 1H), 7.65 (d, J=7.7 Hz,1H), 7.63-7.56 (m, 1H), 2.06 (s, 3H).

Intermediate 87: 4-Fluoro-2-(pyrimidin-2-yl)benzoic Acid

Step A: 2-Iodo-4-fluorobenzonitrile (2.54 g, 10.3 mmol) and2-tributylstannane pyrimidine (3.69 g, 10.0 mmol) were dissolved indimethoxyethane (18 mL) and treated with tetrakistriphenylphosphinepalladium (0) (578 mg, 0.5 mmol) and copper (1) iodide (95 mg, 0.5mmol). The reaction was then heated to 160° C. for 90 minutes in themicrowave. The reaction was cooled, concentrated under reduced pressure.Chromatography (20-100% EA in hexanes) gave the desired product. ¹H NMR(400 MHz, CDCl₃): 8.93 (d, J=4.9 Hz, 2H), 8.14 (dd, J=9.6, 2.7 Hz, 1H),7.86 (dd, J=8.6, 5.3 Hz, 1H), 7.36 (t, J=4.9 Hz, 1H), 7.32-7.23 (m, 1H).

Step: 4-Fluoro-2-(pyrimidin-2-yl)benzonitrile (85 mg, 0.4 mmol) washydrolyzed to the acid in water (1 mL) by addition of 18 M H₂SO₄ (1 mL).The reaction was heated at 100° C. for 10 min, then cooled to 23° C.,and extracted with EtOAc (3×5 mL). The combined organics were dried(Na₂SO₄) and concentrated under reduced pressure. This material was usedcrude in subsequent reactions.

Intermediate 88: 4-Methoxy-2-(pyrimidin-2-yl)benzoic Acid

Step A: 4-Methoxy-2-(pyrimidin-2-yl)benzonitrile was prepared in amanner analogous to Intermediate 87. ¹H NMR (400 MHz, CDCl₃): 8.93 (d,J=4.9 Hz, 2H), 8.14 (dd, J=9.6, 2.7 Hz, 1H), 7.86 (dd, J=8.6, 5.3 Hz,1H), 7.36 (t, J=4.9 Hz, 1H), 7.32-7.23 (m, 1H).

Step B: 4-Methoxy-2-(pyrimidin-2-yl)benzonitrile (85 mg, 0.4 mmol) wasdissolved in MeOH (20 mL) was treated with 2M aq NaOH (15 mL). Thereaction was heated at reflux overnight, the reaction was cooled to roomtemperature and filtered to remove the solids and washed with cold MeOH.The filtrate was concentrated to minimum volume and then acidified topH=3 with 6 N aq. HCl and cooled to 0° C. then filtered and washed withcold water. This material was used crude in subsequent reactions.

Intermediate 89: 2-Chloro-4,4,4,5,6,6,6-septadeuteriopyrimidine

Step A: 1,1,1,3,3,3,5,5-Octadeuteriopentane-2,4-dione. To a solution ofacetylacetone (10 mL, 95.1 mmol) in D₂O (90 mL) was added K₂CO₃ (1.0 g,7.29 mmol). The mixture was heated at 120° C. overnight. The aqueouslayer was extracted with DCM and the combined organic layers were driedover Na₂SO₄, filtered and concentrated in vacuo to an orange liquid(Frediani et. al., Catalysis Comm. 2, 2001, 125).

Step B: 2-Deuteriohydroxy-4,4,4,5,6,6,6-septadeuteriopyrimidine. To asolution of 1,1,1,3,3,3,5,5-Octadeuteriopentane-2,4-dione (product ofStep A) (1.60 g, 14.82 mmol) in EtOD (7 mL) was added urea-d₄ (0.95 g,14.82 mmol) followed by 35% wt. DCl in D₂O (2 mL, 23.71 mmol). Themixture was heated at 90° C. for 36 h, cooled to room temperature andthen chilled in an ice bath before filtration and washing of the whitesolid with cold EtOD to afford the desired product as the DCl salt (1.53g, 61%).

Step C: 2-Chloro-4,4,4,5,6,6,6-septadeuteriopyrimidine. To2-deuteriohydroxy-4,4,4,5,6,6,6-septadeuteriopyrimidine (product of StepB) (1.53 g, 9.04 mmol) was added POCl₃ (7.9 mL, 9.04 mmol) and themixture was heated at reflux for 16 h. The mixture was allowed to coolto room temperature and then added to ice drop wise. The aqueous mixturewas neutralized to pH 6 in an ice bath with 5 N NaOH. The aqueous layerwas extracted with DCM and the combined organic layers were dried overNa₂SO₄, filtered and concentrated in vacuo to afford the desired productas a yellow solid (1.3 g, 96%). (ESI): mass calculated for C₆D₇ClN₂,149.07. m/z found, 150.1.

Intermediate 90: tert-Butyl5-{4,6-bis[(²H₃)methyl](²H)pyrimidin-2-yl}hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

A mixture of Intermediate 15 (294 mg, 1.38 mmol), Intermediate 89 (207mg, 1.38 mmol) and DIPEA (0.48 mL, 2.77 mmol) in ACN (3.5 mL) was heatedin the microwave at 150° C. for 2 h. The mixture was concentrated invacuo. The crude mixture was purified by FCC (Hex to 50% EtOAc/Hex) toafford the title compound (344 mg, 76%). MS (ESI): mass calculated forC₁₇H₁₉D₇N₄O₂, 325.25. m/z found 326.2 [M+1]⁺. ¹H NMR (500 MHz, CDCl₃):3.86-3.76 (m, 2H), 3.67-3.50 (m, 4H), 3.37-3.24 (m, 2H), 2.98-2.90 (m,2H), 1.44 (s, 9H).

Intermediate 91:5-{4,6-Bis[(²H₃)methyl](²H)pyrimidin-2-yl}hexahydropyrrolo[3,4-c]pyrrole

Intermediate 90 (325 mg, 1 mmol), DCM (5 mL) and TFA (1 mL) were stirredat room temperature for 2 h. The mixture was concentrated in vacuo andwas used as is. MS (ESI): mass calculated for C₁₂H₁₁D₇N₄, 225.25. m/zfound 225.2 [M+1]⁺.

Intermediate 92:2-(4,6-Dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole, bis-HClSalt

A 150 mL EasyMax reactor was fitted with a mechanical stirrer, a refluxcondenser and a temperature probe and 2-chloro-4,6-dimethyl pyrimidine(7.10 g, 49.8 mmol), potassium carbonate (9.77 g, 70.7 mmol),N-boc-3,7diazabicylco[3.3.0]octane (10.03 g, 47.3 mmol) and 2-propanol(54.2 g) were added. The reaction was slurried at 20° C. for 5 minutesand then the temperature was raised to 80° C. over 30 minutes. Thereaction was then stirred at 80° C. for 8 hours, cooled to 20° C. within30 minutes and allowed to stand overnight. To the resulting mixture wasadded toluene (15.8 g) and the mixture was stirred at 30° C. for 30minutes prior to removing all salts by suction filtration. The reactorand filter cake were then washed with toluene (20.2 g) and the resultingfiltrates (˜115 mL) were added to a 150 mL EasyMax reactor held at atemperature of 20° C. 5-6 N HCl in 2-propanol (25.90 g) was then addeddropwise over a 30 minute period. The mixture was then heated to 60° C.over 20 minutes and stirred for 4 hours. After approximately 1.5 hourscrystallization of the product started and the yellowish suspension wasthen cooled to 0-5° C. and was then stirred for another 1.5 hours. Theproduct was then isolated via suction filtration and washed with2-propanol (25.0 g) in two portions. The resulting wet product cake wasdried in vacuo at 50° C. overnight then at 70° C. for 4 hours to obtainthe title compound (11.52 g, 77%) as an off-white crystalline solid.Purity was assessed by HPLC (99.5%, 99.7%, and 99.5 area % (at 254, 235,and 280 nm, respectively). HCl content was determined to be 25.26%.

Intermediate 93: 3-Fluoro-2-(1H-pyrazol-1-yl)benzoic Acid

3-Fluoro-2-(1H-pyrazol-1-yl)benzoic acid. To a mixture of3-fluoro-2-iodobenzoic acid (1.4 g, 5.26 mmol), 1H-pyrazole (0.72 g,10.5 mmol), trans-N,N′-dimethyl-cyclohexane-1,2-diamine (0.17 mL, 1.05mmol), CuI (50.1 mg, 0.26 mmol), dioxane (50 mL) and water (0.028 mL)was added Cs₂CO₃ (3.43 g, 10.5 mmol). The reaction mixture was heated to100° C. for 1 h. The reaction mixture was cooled to ambient temperaturethen diluted with water. The aqueous layer was acidified to pH2 andextracted with EtOAc (30 mL) three times. The organic layers werecombined, dried over Na₂SO₄, filtered and concentrated. Purification(FCC), (DCM to 10% MeOH/1% HOAC/DCM) afforded the title compound as acolorless oil (790 mg, 72%). ¹H NMR (400 MHz, CDCl₃): 7.85-7.73 (m, 1H),7.54-7.44 (m, 1H), 7.44-7.34 (m, 1H), 6.55 (s, 1H).

Intermediate 94: 3-Methyl-2-(1H-pyrazol-1-yl)benzoic Acid

The title compound was prepared in a manner analogous to Intermediate 93substituting 3-methyl-2-iodobenzoic acid for 3-fluoro-2-iodobenzoicacid. ¹H NMR (500 MHz, CDCl₃): 7.79 (d, J=7.4 Hz, 2H), 7.48 (d, J=7.5Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 6.53 (s, 1H), 2.07 (s, 3H).

Intermediate 95: 2-Fluoro-6-(pyrimidin-2-yl)benzoic Acid

Step A: 2-Fluoro-6-iodo-benzoic acid methyl ester. To a 200 mLround-bottomed flask were added 2-fluoro-6-iodo-benzoic acid (7.5 g,28.2 mmol), LiOH·H₂O (1.42 g, 33.8 mmol), and THE (100 mL). Theresulting mixture was warmed to 50° C. and stirred for 2 h. Dimethylsulfate (4.03 mL, 42.3 mmol) was then added and the mixture was warmedto 65° C. After 2 h, the mixture was cooled to room temperature andNH₄Cl_((aq)) (50 mL, 13 wt % solution) was added. The two resultinglayers were thoroughly mixed and then separated. The organic layer wasdried over MgSO₄, filtered, and concentrated under reduced pressure to alight brown oil (7.79 g, 99% yield). ¹H NMR (400 MHz, CDCl₃): 7.68-7.60(m, 1H), 7.15-7.06 (m, 2H), 3.98 (s, 3H).

Step B:2-Fluoro-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acidmethyl ester. To a 500 mL round-bottomed flask were added2-fluoro-6-iodo-benzoic acid methyl ester (7.29, 26.0 mmol) andanhydrous THF (150 mL). This mixture was cooled to 0° C. and i-PrMgCl(13.7 mL, 2 M in THF, 27.3 mmol) was added dropwise. After 10 min,2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.58 mL, 27.3mmol) was added. The mixture was allowed to warm to room temperature,and after 30 min NH₄Cl_((aq)) (150 mL, 13 wt % solution) was added. Thelayers were mixed and then separated, and the aqueous layer wasextracted with 100 mL of MTBE. The combined organic layers were driedover Na₂SO₄, filtered, and concentrated to a final mass of 6.07 g (90%wt %, 75% yield). ¹H NMR (400 MHz, CDCl₃): 7.47-7.38 (m, 2H), 7.17-7.11(m, 1H), 3.92 (s, 3H), 1.36 (s, 12H).

Step C: 2-Fluoro-6-pyrimidin-2-yl-benzoic acid methyl ester. To a 250 mLround-bottomed flask under nitrogen were added2-fluoro-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acidmethyl ester (5.46 g, 19.5 mmol) in 2-methyl-THF (50 mL),2-chloropyrimidine (2.68 g, 23.4 mmol), and sodium carbonate (6.2 g,58.5 mmol) in water (17 mL). PdCl₂(dppf)-dcm adduct (CAS #72287-26-4)(1.27 g, 1.56 mmol) was then added and the reaction mixture was warmedto 74° C. and stirred for 2.5 h. After cooling, the mixture was dilutedwith MTBE (50 mL) and water (80 mL). The layers were thoroughly mixedseparated. The aqueous layer was extracted with additional MTBE (100mL). The combined organics were dried over magnesium sulfate, filtered,concentrated and then purified by flash chromatography (0-25%EA/hexanes) to provide the title compound (1.72 g, 72 wt %, 30% yield).¹H NMR (400 MHz, CDCl₃): 8.79 (d, J=4.9 Hz, 2H), 8.15 (d, J=7.9 Hz, 1H),7.51 (td, J=8.1, 5.6 Hz, 1H), 7.28-7.20 (m, 2H), 3.92 (s, 3H).

Step D: 2-Fluoro-6-pyrimidin-2-yl-benzoic acid. To a solution of2-fluoro-6-pyrimidin-2-yl-benzoic acid methyl ester (1.36 g, 5.85 mmol)in 2-methyl-THF (20 mL) was added sodium hydroxide (2 M in water, 9.3mL, 18.6 mmol). The mixture was heated to 72° C. and stirred for 9 h.The layers were separated and the aqueous layer acidified to pH 2 bydropwise addition of 50% HCl_((aq)) (3.1 mL). The resulting solids werestirred for 1 h, filtered, washed with water, MTBE, and heptanes, andthen dried to provide the desired product as a white solid (1.12 g, 88%yield). ¹H NMR (400 MHz, CD₃OD): 8.83 (d, J=4.9 Hz, 2H), 8.03 (dd,J=7.9, 0.8 Hz, 1H), 7.59 (td, J=8.1, 5.6 Hz, 1H), 7.40 (t, J=4.9 Hz,1H), 7.34 (ddd, J=9.4, 8.4, 1.0 Hz, 1H).

Intermediate 96: 3-Methyl-2-(1H-1,2,3-triazol-1-yl)benzonitrile

The title compound was a byproduct of the synthesis of Intermediate 81(3.1 g, 56%). MS (ESI) mass calcd. for C₁₀H₈N₄, 184.2. m/z found, 185.1[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.94 (d, J=2.1 Hz, 1H), 7.87 (d, J=1.1Hz, 1H), 7.71-7.67 (m, 1H), 7.67-7.62 (m, 1H), 7.56 (dd, J=9.7, 5.8 Hz,1H), 2.17 (s, 3H).

Intermediate 97: 5-Fluoro-2-[1,2,3]triazol-2-yl-benzoic Acid

5-Fluoro-2-[1,2,3]triazol-2-yl-benzoic acid. To a solution of5-fluoro-2-iodo-benzoic acid (3.86 g, 14.65 mmol), 2H-[1,2,3]triazole(2.5 g, 36.2 mmol), Cs₂CO₃ (8.62 g, 24.5 mmol),trans-N,N′-dimethyl-cyclohexane-1,2-diamine (0.4 mL), CuI (244 mg) andDMF (13 mL) were added to a microwave ready vessel and heated to 100° C.for 10 min. The mixture was cooled, diluted with water, and extractedwith EtOAc. The aqueous layer was acidified and extracted with EtOAc.The organic layer was dried over Na₂SO₄ and concentrated. The residuewas purified by FCC (SiO₂, gradient DCM to 10% MeOH/1% HOAc/DCM) gavethe product as a white powder, (2.14 g, 71%). ¹H NMR (400 MHz, CD₃OD):7.91 (s, 2H), 7.76 (dd, J=8.9, 4.8 Hz, 1H), 7.59 (dd, J=8.5, 2.9 Hz,1H), 7.49-7.42 (m, 1H).

Example 1:4-[5-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6-methoxy-N,N-dimethylpyrimidin-2-amine

A mixture of[4-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]-dimethyl-amine(60.0 mg, 0.23 mmol), 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (52.0mg, 0.25 mmol), HATU (130.0 mg, 0.34 mmol) and DIPEA (0.12 mL, 0.68mmol) was stirred into DMF (4.0 mL) at room temperature for 30 minutes.The reaction mixture was diluted with ethyl acetate (60.0 mL) and washedwith water (2×100 mL). The organic phase was dried (Na₂SO₄), filteredand concentrated to dryness to yield crude title compound (354.0 mg,343%). The crude product was purified using Agilent HPLC (Basic system)to yield pure title compound (84.0 mg, 81.5%). MS (ESI) mass calcd. forC₂₂H₂₅FN₈O₂, 452.49. m/z found 453.3 [M+H]⁺. ¹H NMR (CDCl₃): 7.88-7.79(m, 2H), 7.72 (d, J=6.7, 1H), 7.54-7.41 (m, 1H), 7.19-7.08 (m, 1H),5.02-4.92 (m, 1H), 3.96-3.86 (m, 1H), 3.87-3.83 (m, 3H), 3.81-3.50 (m,5H), 3.43-3.19 (m, 2H), 3.15-3.09 (m, 6H)), 3.09-2.91 (m, 2H).

Example 2:N,N-Dimethyl-6-[5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2-(trifluoromethyl)pyrimidin-4-amine

A mixture of[6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl]-dimethyl-amine(50 mg, 0.17 mmol), 2-[1,2,3]triazol-2-yl-benzoic acid (34.5 mg, 0.18mmol), HATU (94.6 mg, 0.25 mmol) and DIPEA (0.09 mL, 0.50 mmol) in DMF(4.0 mL) was stirred at room temperature for 30 minutes. The reactionmixture was diluted with ethyl acetate (60.0 mL) and washed with water(2×100 mL). The organic phase was dried (Na₂SO₄), filtered andconcentrated to dryness. The crude product was purified using AgilentHPLC (Basic system) to yield pure title compound (34.0 mg, 43.4%). MS(ESI) mass calcd. for C₂₂H₂₃F₃N₅O, 472.47. m/z found 473.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.98 (d, J=8.1, 1H), 7.70-7.69 (m, 2H), 7.56-7.49 (m, 1H),7.45-7.37 (m, 2H), 5.20-5.10 (m, 1H), 3.90-3.66 (m, 4H), 3.60-3.28 (m,4H), 3.08 (s, 6H), 3.02-2.89 (m, 2H).

Example 3:6-[5-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-N,N-dimethyl-2-(trifluoromethyl)pyrimidin-4-amine

A mixture of[6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl]-dimethyl-amine(50 mg, 0.17 mmol), 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (37.8mg, 0.18 mmol), HATU (94.6 mg, 0.25 mmol) and DIPEA (0.09 mL, 0.50 mmol)in DMF (4.0 mL) was stirred at room temperature for 30 minutes. Thereaction mixture was diluted with ethyl acetate (60.0 mL) and washedwith water (2×100 mL). The organic phase was dried (Na₂SO₄), filteredand concentrated to dryness. The crude product was purified usingAgilent HPLC (Basic system) to yield pure title compound (19.0 mg,23.4%). MS (ESI) mass calcd. for C₂₂H₂₂F₄N₅O, 490.46. m/z found [M+H]⁺.¹H NMR (CDCl₃): 7.89-7.79 (m, 2H), 7.74 (s, 1H), 7.55-7.37 (m, 1H),7.21-7.05 (m, 1H), 5.25-5.09 (m, 1H), 4.25-3.51 (m, 6H), 3.50-2.95 (m,10H).

Example 4:4-[5-{[5-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6-methoxy-N,N-dimethylpyrimidin-2-amine

A mixture of[4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]-dimethyl-amine(60.0 mg, 0.23 mmol), 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (52.0mg, 0.25 mmol), HATU (130.0 mg, 0.34 mmol) and DIPEA (0.12 mL, 0.68mmol) was stirred into DMF (4.0 mL) at room temperature for 30 minutes.The reaction mixture was diluted with ethyl acetate (60.0 mL) and washedwith water (2×100 mL). The organic phase was dried (Na₂SO₄), filteredand concentrated to dryness. The crude product was purified usingAgilent HPLC (Basic system) to yield pure title compound (160.0 mg,54%). MS (ESI) mass calcd. for C₂₂H₂₅FN₈O₂, 452.49. m/z found 453.3[M+H]⁺. ¹H NMR (CDCl₃): 7.95 (dd, J=9.0, 4.8, 1H), 7.73 (s, 2H),7.25-7.17 (m, 1H), 7.16-7.10 (m, 1H), 5.00-4.90 (m, 1H), 3.92-3.78 (m,4H), 3.76-3.25 (m, 6H), 3.18-3.07 (m, 6H), 3.05-2.86 (m, 3H).

Example 5:4-Methoxy-N,N-dimethyl-6-[5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo-[3,4-c]pyrrol-2(1H)-yl]pyrimidin-2-amine

A mixture of[4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]-dimethyl-amine(60.0 mg, 0.23 mmol), 2-[1,2,3]triazol-2-yl-benzoic acid (47.4 mg, 0.25mmol), HATU (130.0 mg, 0.34 mmol) and DIPEA (0.12 mL, 0.68 mmol) wasstirred into DMF (4.0 mL) at room temperature for 30 minutes. Thereaction mixture was diluted with ethyl acetate (60.0 mL) and washedwith water (2×100 mL). The organic phase was dried (Na₂SO₄), filteredand concentrated to dryness. The crude product was purified usingAgilent HPLC (Basic system) to yield pure title compound (47.0 mg,47.5%). MS (ESI) mass calcd. for C₂₂H₂₆NO₂, 434.5. m/z found [M+H]⁺. ¹HNMR (CDCl₃): 7.98 (d, J=8.1, 1H), 7.73 (s, 2H), 7.75 (s, 2H), 7.55-7.47(m, 1H), 7.45-7.37 (m, 2H), 5.00-4.90 (m, 1H), 3.91-3.80 (m, 5H), 3.70(dd, J=12.5, 3.9, 2H), 3.60-3.29 (m, 4H), 3.19-3.04 (m, 8H).

Example 6:6-[5-{[4-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-N,N-dimethyl-2-(trifluoromethyl)pyrimidin-4-amine

A mixture of[6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl]-dimethyl-amine(50 mg, 0.17 mmol), 4-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (37.8mg, 0.18 mmol), HATU (94.6 mg, 0.25 mmol) and DIPEA (0.09 mL, 0.50 mmol)in DMF (4.0 mL) was stirred at room temperature for 30 minutes. Thereaction mixture was diluted with ethyl acetate (60.0 mL) and washedwith water (2×100 mL). The organic phase was dried (Na₂SO₄), filteredand concentrated to dryness. The crude product was purified usingAgilent HPLC (Basic system) to yield pure title compound (42.0 mg,51.6%). MS (ESI) mass calcd. for C₂₂H₂₂F₄N₈O, 490.46; m/z found [M+H]⁺.¹H NMR (CDCl₃): 7.90-7.65 (m, 3H), 7.57-7.35 (m, 1H), 7.18-7.02 (m, 1H),5.23-5.05 (m, 1H), 4.02-3.20 (m, 7H), 3.16-2.84 (m, 9H).

Example 7:4-[5-{[4-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6-methoxy-N,N-dimethylpyrimidin-2-amine

A mixture of[4-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6-methoxy-pyrimidin-2-yl]-dimethyl-amine(60.0 mg, 0.23 mmol), 4-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (52.0mg, 0.25 mmol), HATU (130.0 mg, 0.34 mmol) and DIPEA (0.12 mL, 0.68mmol) was stirred into DMF (4.0 mL) at room temperature for 30 minutes.The reaction mixture was diluted with ethyl acetate (60.0 mL) and washedwith water (2×100 mL). The organic phase was dried (Na₂SO₄), filteredand concentrated to dryness. The crude product was purified usingAgilent HPLC (Basic system) to yield pure title compound (52.0 mg,50.5%). MS (ESI) mass calcd. for C₂₂H₂₅FN₈O₂, 452.49; m/z found [M+H]⁺.¹H NMR (CDCl₃): 7.83-7.66 (m, 3H), 7.42-7.36 (m, 1H), 7.16-7.08 (m, 1H),5.00-4.89 (m, 1H), 3.90-3.78 (m, 4H), 3.77-3.19 (m, 6H), 3.17-2.82 (m,9H).

Example 8:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-(1H-pyrrol-1-yl)thiophen-2-yl]carbonyl}octahydro-pyrrolo[3,4-c]pyrrole

A mixture of2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (60.0mg, 0.28 mmol), 3-pyrrol-1-yl-thiophene-2-carboxylic acid (58.4 mg, 0.30mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (106.6 mg, 0.83 mmol) wasstirred into DMF (5.0 mL) at room temperature for 30 minutes. Thereaction mixture was diluted with ethyl acetate (60.0 mL) and washedwith water (2×100 mL). The organic phase was dried (Na₂SO₄), filteredand concentrated to dryness. The crude product was purified usingAgilent HPLC (Basic system) to yield pure title compound (79.0 mg, 73%).MS (ESI) mass calcd. for C₂₁H₂₃N₅OS, 393.51. m/z found [M+H]⁺. ¹H NMR(CDCl₃): 7.42-7.39 (m, 1H), 7.04-7.01 (m, 1H), 6.85 (t, J=2.1, 2H), 6.29(s, 1H), 6.14 (t, J=2.1, 2H), 3.88-3.73 (m, 2H), 3.66-3.52 (m, 2H),3.50-3.41 (m, 1H), 3.32-3.20 (m, 1H), 3.00-2.86 (m, 2H), 2.80-2.66 (m,1H), 2.60-2.47 (m, 1H), 2.34-2.25 (m, 6H).

Example 9:6-[5-{[5-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-N,N-dimethyl-2-(trifluoromethyl)pyrimidin-4-amine

A mixture of[6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl]-dimethyl-amine(50 mg, 0.17 mmol), 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (37.8mg, 0.18 mmol), HATU (94.6 mg, 0.25 mmol) and DIPEA (0.09 mL, 0.50 mmol)in DMF (4.0 mL) was stirred at room temperature for 30 minutes. Thereaction mixture was diluted with ethyl acetate (60.0 mL) and washedwith water (2×100 mL). The organic phase was dried (Na₂SO₄), filteredand concentrated to dryness. The crude product was purified usingAgilent HPLC (Basic system) to yield pure title compound (42.0 mg,51.6%). MS (ESI) mass calcd. for C₂₂H₂₂F₄N₈O, 490.46. m/z found [M+H]⁺.¹H NMR (CDCl₃): 7.96 (dd, J=9.0, 4.8, 1H), 7.80-7.66 (m, 2H), 7.25-7.18(m, 1H), 7.16-7.10 (m, 1H), 5.22-5.11 (m, 1H), 3.90-3.30 (m, 8H),3.13-3.06 (m, 7H), 3.00 (s, 6H).

Example 10:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(1-phenyl-1H-pyrazol-5-yl)carbonyl]octahydropyrrolo[3:4-c]pyrrole

A mixture of2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (60.0mg, 0.28 mmol), 2-phenyl-2H-pyrazole-3-carboxylic acid (56.9 mg, 0.30mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (106.6 mg, 0.83 mmol) wasstirred into DMF (5.0 mL) at room temperature for 30 minutes. Thereaction mixture was diluted with ethyl acetate (60.0 mL) and washedwith water (2×100 mL). The organic phase was dried (Na₂SO₄), filteredand concentrated to dryness. The crude product was purified usingAgilent HPLC (Basic system) to yield pure title compound (79.0 mg, 74%).MS (ESI) mass calcd. for C₂₂H₂₄N₆O, 388.47. m/z found 389.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.67 (d, J=1.7, 1H), 7.50 (d, J=7.4, 2H), 7.37 (t, J=7.8,2H), 7.29-7.23 (m, 1H), 6.56 (d, J=1.7, 1H), 6.30 (s, 1H), 3.86-3.71 (m,2H), 3.70-3.51 (m, 2H), 3.43-3.22 (m, 3H), 3.05-2.77 (m, 3H), 2.29 (s,6H).

Example 11:8-{[5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]carbonyl}-quinoline

A mixture of2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (60.0mg, 0.28 mmol), quinoline-8-carboxylic acid (52.4 mg, 0.30 mmol), HATU(156.8 mg, 0.41 mmol) and DIPEA (106.6 mg, 0.83 mmol) was stirred intoDMF (5.0 mL) at room temperature for 30 minutes. The reaction mixturewas diluted with ethyl acetate (60.0 mL) and washed with water (2×100mL). The organic phase was dried (Na₂SO₄), filtered and concentrated todryness. The crude product was purified using Agilent HPLC (Basicsystem) to yield pure title compound (68.0 mg, 66.2%). MS (ESI) masscalcd. for C₂₂H₂₃N₅O, 373.46. m/z found 374.2 [M+H]⁺. ¹H NMR (CDCl₃):8.95 (s, 1H), 8.16 (d, J=7.9, 1H), 7.89-7.79 (m, 1H), 7.69 (d, J=6.8,1H), 7.61-7.49 (m, 1H), 7.41 (s, 1H), 6.26 (d, J=19.1, 1H), 4.29-4.03(m, 1H), 3.96-3.59 (m, 4H), 3.65-3.29 (m, 2H), 3.21-2.84 (m, 3H),2.37-2.18 (m, 6H).

Example 12:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(3-phenylthiophen-2-yl)carbonyl]octahydropyrrolo[3,4-c]pyrrole

A mixture of2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (60.0mg, 0.28 mmol), 3-phenyl-thiophene-2-carboxylic acid (61.8 mg, 0.30mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (107.0 mg, 0.83 mmol) wasstirred into DMF (5.0 mL) at room temperature for 30 minutes. Thereaction mixture was diluted with ethyl acetate (60.0 mL) and washedwith water (2×100 mL). The organic phase was dried (Na₂SO₄), filteredand concentrated to dryness. The crude product was purified usingAgilent HPLC (Basic system) to yield pure title compound (30.0 mg,27.0%). MS (ESI) mass calcd. for C₂₃H₂₄N₄OS, 404.54. m/z found 405.2[M+H]⁺. ¹H NMR (CDCl₃): 7.45-7.41 (m, 2H), 7.39-(d, J=5.1, 1H),7.34-7.27 (m, 2H), 7.18-7.14 (m, 1H), 7.13 (d, J=5.0, 1H), 6.28 (s, 1H),3.88-3.66 (m, 2H), 3.61-3.49 (m, 2H), 3.30 (dd, J=11.5, 5.1, 1H),3.19-3.04 (m, 2H), 2.92-2.78 (m, 1H), 2.75-2.61 (m, 2H), 2.37-2.22 (m,6H).

Example 13:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(3-phenylfuran-2-yl)carbonyl]octahydropyrrolo[3,4-c]pyrrole

A mixture of2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (60.0mg, 0.28 mmol), 3-phenyl-furan-2-carboxylic acid (61.8 mg, 0.30 mmol),HATU (156.8 mg, 0.41 mmol) and DIPEA (107.0 mg, 0.83 mmol) was stirredinto DMF (5.0 mL) at room temperature for 30 minutes. The reactionmixture was diluted with ethyl acetate (60.0 mL) and washed with water(2×100 mL). The organic phase was dried (Na₂SO₄), filtered andconcentrated to dryness. The crude product was purified using DionexHPLC to yield pure title compound (30.0 mg, 28.0%). MS (ESI) mass calcd.for C₂₃H₂₄N₄O₂, 388.47. m/z found 389.2 [M+H]⁺. ¹H NMR (CDCl₃):7.56-7.50 (m, 2H), 7.46 (d, J=1.8, 1H), 7.37-7.30 (m, 2H), 7.25-7.19 (m,1H), 6.61 (d, J=1.8, 1H), 6.29 (s, 1H), 3.95-3.80 (m, 2H), 3.75-3.60 (m,3H), 3.51 (dd, J=11.6, 5.01H), 3.42 (dd, J=11.6, 4.1, 1H), 3.33 (dd,J=11.6, 5.4, 1H), 3.02-2.81 (m, 2H), 2.35-2.22 (m, 6H).

Example 14:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-(1H-1,2,4-triazol-5-yl)phenyl]carbonyl}octahydro-pyrrolo[3,4-c]pyrrole

A mixture of2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (60.0mg, 0.28 mmol), 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid (57.2 mg, 0.30mmol), HATU (156.8 mg, 0.41 mmol) and DIPEA (107.0 mg, 0.83 mmol) wasstirred into DMF (5.0 mL) at room temperature for 30 minutes. Thereaction mixture was diluted with ethyl acetate (60.0 mL) and washedwith water (2×100 mL). The organic phase was dried (Na₂SO₄), filteredand concentrated to dryness. The crude product was purified usingAgilent HPLC (basic system) to yield pure title compound (60.0 mg, 56%).MS (ESI) mass calcd. for C₂₁H₂₃N₇O, 389.46. m/z found 390.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.12 (d, J=7.5, 1H), 8.05 (s, 1H), 7.53-7.39 (m, 2H),7.37-7.31 (m, 1H), 6.28 (s, 1H), 3.95-3.77 (m, 2H), 3.76-3.55 (m, 3H),3.48-3.33 (m, 2H), 3.19-3.03 (m, 1H), 3.02-2.95 (m, 1H), 2.91-2.82 (m,1H), 2.36-2.19 (m, 6H).

Example 15:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

A mixture of2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (437.3mg, 2.0 mmol), 3-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (415 mg, 2.0mmol), HATU (1.14 g, 3.0 mmol) and DIPEA (777 mg, 6.0 mmol) was stirredinto DMF (20 mL) at room temperature for 30 minutes. The reactionmixture was diluted with ethyl acetate (250 mL) and washed with water(2×500 mL). The organic phase was dried (Na₂SO₄), filtered andconcentrated to dryness. The crude product was purified using AgilentHPLC (basic system) to yield pure title compound (458.0 mg, 56%). MS(ESI) mass calcd. for C₂₁H₂₂FN₇O, 407.45. m/z found 408.2 [M+H]⁺. ¹H NMR(CDCl₃): 7.79 (s, 2H), 7.52-7.45 (m, 1H), 7.36-7.28 (m, 1H), 7.25-7.22(m, 1H), 6.30 (s, 1H), 3.82 (dd, J=11.6, 7.5, 1H), 3.75-3.66 (m, 2H),3.58-3.41 (m, 4H), 3.13 (dd, J=10.9, 5.2, 1H), 3.02-2.87 (m, 2H),2.36-2.24 (m, 6H).

Examples 16-106, 108-214 were prepared in a manner analogous to Example15.

Example 16:2-{5-[(2,4-Dimethoxyphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-6-fluoro-1,3-benzothiazole

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 38 and 2-chloro-6-fluoro-benzothiazole. MS (ESI)mass calcd. for C₂₂H₂₂FN₃O₃S, 427.5. m/z found, 428.2 [M+H]⁺.

Example 17:2-{5-[(2,4-Dimethoxyphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1,3-benzothiazole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 38 and 2-chloro-benzothiazole. MS (ESI) masscalcd. for C₂₂H₂₃N₃O₃S, 409.51. m/z found, 410.2 [M+H]⁺.

Example 18:2-[5-{[2-(1H-Pyrazol-1-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 2-pyrazol-1-yl-benzoic acid. MS (ESI) masscalcd. for C₂₄H₂₂N₆O, 410.48. m/z found, 411.2 [M+H]⁺.

Example 19:2-{5-[(2-Thiophen-2-ylphenyl)carbonyl]hexahydropyrrolo[34-c]pyrrol-2(1H)-yl}quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 2-thiophen-2-yl-benzoic acid. MS (ESI)mass calcd. for C₂₅H₂₂N₄OS, 426.54. m/z found, 427.2 [M+H]⁺.

Example 20:2-{5-[(2-Methylnaphthalen-1-yl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 2-methyl-naphthalene-1-carboxylic acid. MS(ESI) mass calcd. for C₂₅H₂₂N₄OS, 426.54. m/z found, 427.2 [M+H]⁺.

Example 21:2-(2,3-Dihydro-1,4-benzodioxin-5-ylcarbonyl)-5-(4-phenylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 26 and 2,3-dihydro-benzo[1,4]dioxine-5-carboxylicacid. MS (ESI) mass calcd. for C₂₅H₂₄N₄O₃, 428.50. m/z found, 429.2[M+H]⁺.

Example 22:2-(4-Phenylpyrimidin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 26 and 2-thiophen-2-yl-benzoic acid. MS (ESI)mass calcd. for C₂₇H₂₄N₄OS, 452.58. m/z found, 453.2 [M+H]⁺.

Example 23:2-(4-Phenylpyrimidin-2-yl)-5-{[2-(1H-pyrazol-1-yl)phenyl]carbonyl}octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 26 and 2-pyrazol-1-yl-benzoic acid. MS (ESI) masscalcd. for C₂₆H₂₄N₆, 436.52. m/z found, 437.2 [M+H]⁺.

Example 24:2-(4-Phenylpyrimidin-2-yl)-5-{[2-(1H-pyrrol-1-yl)phenyl]carbonyl}octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 26 and 2-pyrrol-1-yl-benzoic acid. MS (ESI) masscalcd. for C₂₇H₂₅N₅O, 435.53. m/z found, 436.3 [M+H]⁺.

Example 25:2-[(2-Methylnaphthalen-1-yl)carbonyl]-5-(4-phenylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 26 and 2-methyl-naphthalene-1-carboxylic acid. MS(ESI) mass calcd. for C₂₈H₂₆N₄O, 434.51. m/z found, 435.3 [M+H]⁺.

Example 26:2-(5-Quinoxalin-2-yl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl)-benzonitrile

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 2-cyano-benzoic acid. MS (ESI): masscalculated for C₂₂H₁₉N₅O, 369.43. m/z found 370.3 [M+H]⁺.

Example 27:2-[5-{[2-(1H-Pyrrol-1-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 2-pyrrol-1-yl-benzoic acid. MS (ESI) masscalcd. for C₂₅H₂₃N₅O, 409.49. m/z found, 410.2 [M+H]⁺.

Example 28:2-{5-[(4′-Fluorobiphenyl-2-yl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 4′-fluoro-biphenyl-2-carboxylic acid. MS(ESI) mass calcd. for C₂₇H₂₃FN₄O, 438.51. m/z found, 439.2 [M+H]⁺.

Example 29:2-{5-[(3′-Fluorobiphenyl-2-yl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 3′-fluoro-biphenyl-2-carboxylic acid. MS(ESI) mass calcd. for C₂₇H₂₃FN₄O, 438.51. m/z found, 439.2 [M+H]⁺.

Example 30:2-{5-[(2-Methylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 2-methylbenzoic acid. MS (ESI) mass calcd.for C₂₂H₂₂N₄O, 358.45. m/z found, 359.2 [M+H]⁺.

Example 31:2-(Biphenyl-2-ylcarbonyl)-5-(4-furan-2-ylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 17 and 2-chloro-4-furan-2-yl-pyrimidine. MS (ESI)mass calcd. for C₂₇H₂₄N₄O₂, 436.52. m/z found, 437.2 [M+H]⁺.

Example 32:2-(4-Methylpyrimidin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 37 and 2-chloro-4-methyl-pyrimidine. MS (ESI)mass calcd. for C₂₂H₂₂N₄OS, 390.51. m/z found, 391.2 [M+H]⁺.

Example 33:2-{5-[(2-Thiophen-2-ylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}quinoline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 37 and 2-chloro-quinoline. MS (ESI) mass calcd.for C₂₆H₂₃N₃OS, 425.56. m/z found, 426.2 [M+H]⁺.

Example 34:2-(4-Furan-2-ylpyrimidin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 37 and 2-chloro-4-furan-2-yl-pyrimidine. MS (ESI)mass calcd. for C₂₅H₂₂N₄O₂S, 442.50. m/z found, 443.2 [M+H]⁺.

Example 35:2-{5-[(2-Ethylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 2-ethylbenzoic acid. MS (ESI) mass calcd.for C₂₃H₂₄N₄O, 372.46. m/z found, 373.2 [M+H]⁺.

Example 36:2-[5-(1H-Indol-7-ylcarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 1H-indole-7-carboxylic acid. MS (ESI) masscalcd. for C₂₃H₂₁N₅O, 383.45. m/z found, 384.2 [M+H]⁺.

Example 37:2-[(2-Thiophen-2-ylphenyl)carbonyl]-5-(4-thiophen-2-ylpyrimidin-2-yl)octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 37 and 2-chloro-4-thiophen-2-yl-pyrimidine. MS(ESI) mass calcd. for C₂₅H₂₂N₄OS₂, 458.60. m/z found, 459.1 [M+H]⁺.

Example 38:2-(Biphenyl-2-ylcarbonyl)-5-(4-thiophen-2-ylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 17 and 2-chloro-4-thiophen-2-yl-pyrimidine. MS(ESI) mass calcd. for C₂₇H₂₄N₄OS, 452.57. m/z found, 453.1 [M+H]⁺.

Example 39:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-[2-(1-methyl-1H-imidazol-2-yl)-phenyl]-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2-(1-methyl-1H-imidazol-2-yl)-benzoicacid. MS (ESI) mass calcd. for C₂₃H₂₆N₆O, 402.50. m/z found, 403.2[M+H]⁺.

Example 40:2-[(2-Bromophenyl)carbonyl]-5-(4-phenylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 26 and 2-bromobenzoic acid. MS (ESI) mass calcd.for C₂₃H₂₁BrN₄O, 449.34. m/z found, 449.1, 451.1 [M+H]⁺.

Example 41:2-{5-[(3′-Chlorobiphenyl-2-yl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 3′-chloro-biphenyl-2-carboxylic acid. MS(ESI) mass calcd. for C₂₇H₂₃ClN₄O, 454.95. m/z found, 455.1 [M+H]⁺.

Example 42:2-{5-[(2-Bromophenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 2-bromobenzoic acid. MS (ESI) mass calcd.for C₂₁H₁₉BrN₄O, 423.31. m/z found, 423.0, 425.0 [M+H]⁺.

Example 43:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 37 and 2-chloro-4,6-dimethyl-pyrimidine. MS (ESI)mass calcd. for C₂₃H₂₄N₄OS, 404.53. m/z found, 405.1 [M+H]⁺.

Example 44:2-(Biphenyl-2-ylcarbonyl)-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 17 and 2-chloro-4,6-dimethyl-pyrimidine. MS (ESI)mass calcd. for C₂₅H₂₆N₄O, 398.5. m/z found, 399.2 [M+H]⁺.

Example 45:2-(4-Methoxypyrimidin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 37 and 2-chloro-4-methoxy-pyrimidine. MS (ESI)mass calcd. for C₂₂H₂₂N₄O₂S, 406.50. m/z found, 407.0 [M+H]⁺.

Example 46:6-Fluoro-2-{5-[(2-thiophen-2-ylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1,3-benzothiazole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 37 and 2-chloro-6-fluoro-benzothiazole. MS (ESI)mass calcd. for C₂₄H₂₀FN₃OS₂, 449.57. m/z found, 450.0 [M+H]⁺.

Example 47:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(2-methylnaphthalen-1-yl)carbonyl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to for Example 15utilizing Intermediate 23 and 2-methyl-naphthalene-1-carboxylic acid. MS(ESI) mass calcd. for C₂₄H₂₆N₄O, 386.5. m/z found, 387.3 [M+H]⁺.

Example 48:2-[(3′-Fluorobiphenyl-2-yl)carbonyl]-5-(4-methylpyrimidin-2-yl)octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 27 and 3′-fluoro-biphenyl-2-carboxylic acid. MS(ESI) mass calcd. for C₂₄H₂₃FN₄O, 402.46. m/z found, 403.1 [M+H]⁺.

Example 49:2-(4-Methoxypyrimidin-2-yl)-5-[(2-methylnaphthalen-1-yl)carbonyl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 32 and 2-methyl-naphthalene-1-carboxylic acid. MS(ESI) mass calcd. for C₂₃H₂₄N₄O₂, 388.46. m/z found, 389.1 [M+H]⁺.

Example 50:2-[(2-Methylnaphthalen-1-yl)carbonyl]-5-(4-methylpyrimidin-2-yl)octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing and 2-methyl-naphthalene-1-carboxylic acid. MS (ESI) masscalcd. for C₂₃H₂₄N₄O, 372.46. m/z found, 373.1 [M+H]⁺.

Example 51:2-[(3′-Fluorobiphenyl-2-yl)carbonyl]-5-(4-methoxypyrimidin-2-yl)octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 32 and 3′-fluoro-biphenyl-2-carboxylic acid. MS(ESI) mass calcd. for C₂₄H₂₃FN₄O₂, 418.46. m/z found, 419.1 [M+H]⁺.

Example 52:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(3′-fluorobiphenyl-2-yl)carbonyl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 3′-fluoro-biphenyl-2-carboxylic acid. MS(ESI) mass calcd. for C₂₅H₂₅FN₄O, 416.49. m/z found, 417.1 [M+H]⁺.

Example 53:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-phenyl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2-fluorobenzoic acid. MS (ESI) mass calcd.for C₁₉H₂₁FN₄O, 340.4. m/z found, 341.2 [M+H]⁺.

Example 54:2-(4-Methoxypyrimidin-2-yl)-5-[(4′-methylbiphenyl-2-yl)carbonyl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 32 and 4′-methyl-biphenyl-2-carboxylic acid. MS(ESI) mass calcd. for C₂₅H₂₆N₄O₂, 414.50. m/z found, 415.1 [M+H]⁺. ¹HNMR (CDCl₃): 8.06 (d, J=5.7 Hz, 1H), 7.54-7.34 (m, 6H), 7.17 (s, 2H),6.01 (d, J=5.7 Hz, 1H), 3.90 (s, 3H), 3.82-3.66 (m, 2H), 3.65-3.35 (m,2H), 3.25-2.55 (m, 6H), 2.33 (s, 3H).

Example 55:2-[(3′-Chlorobiphenyl-2-yl)carbonyl]-5-(4-methoxypyrimidin-2-yl)octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 32 and 3′-chloro-biphenyl-2-carboxylic acid. MS(ESI) mass calcd. for C₂₄H₂₃ClN₄O₂, 434.92. m/z found, 435.1 [M+H]⁺. ¹HNMR (CDCl₃): 8.06 (d, J=5.6 Hz, 1H), 7.55-7.33 (m, 6H), 7.32-7.14 (m,2H), 6.03 (d, J=5.7 Hz, 1H), 3.92 (s, 3H), 3.81-3.64 (m, 2H), 3.61-3.45(m 2H), 3.14 (br s, 3H), 2.91-2.55 (m, 3H).

Example 56:2-[(2-Ethoxynaphthalen-1-yl)carbonyl]-5-(4-methoxypyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared according to the procedure used forExample 15 utilizing Intermediate 32 and2-ethoxy-naphthalene-1-carboxylic acid. MS (ESI) mass calcd. forC₂₄H₂₆N₄O₃, 418.49. m/z found, 419.3 [M+H]⁺. ¹H NMR (CDCl₃): rotamersobserved, 8.07 (t, J=6.3 Hz, 1H), 7.89-7.76 (m, 2H), 7.74 (d, J=8.4 Hz,0.6H), 7.66 (d, J=8.4 Hz, 0.4H), 7.50 (t, J=7.6 Hz, 0.6H), 7.46-7.32 (m,1.5H), 7.31-7.22 (m, 1H), 6.05-6.00 (m, 1H), 4.32-3.81 (m, 7.7H),3.80-3.52 (m, 3.0H), 3.43-3.31 (m, 1H), 3.27 (dd, J=11.1, 5.9 Hz, 0.6H),3.19-3.07 (m, 1H), 3.05-2.92 (m 1.5H), 1.46 (t, J=7.0 Hz, 1.3H), 1.36(t, J=6.9 Hz, 1.8H).

Example 57:2-[(4-Fluoronaphthalen-1-yl)carbonyl]-5-(4-methoxypyrimidin-2-yl)octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 32 and 4-fluoro-naphthalene-1-carboxylic acid. MS(ESI) mass calcd. for C₂₂H₂₁FN₄O₂, 392.43. m/z found, 393.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.22-8.13 (m, 1H), 8.08 (d, J=5.7 Hz, 1H), 7.89 (d, J=7.7Hz, 1H), 7.66-7.53 (m, 2H), 7.43 (dd, J=7.8, 5.3 Hz, 1H), 7.17 (dd,J=10.1, 7.9 Hz, 1H), 6.04 (d, J=5.7 Hz, 1H), 4.11 (dd, J=12.8, 7.8 Hz,1H), 4.00-3.80 (m, 5H), 3.80-3.63 (m, 2H), 3.57-3.39 m, 2H), 3.22-3.08(m, 2H), 3.04-2.92 (m, 1H).

Example 58:2-(4-Methoxypyrimidin-2-yl)-5-(naphthalen-1-ylcarbonyl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 32 and naphthalene-1-carboxylic acid. MS (ESI)mass calcd. for C₂₂H₂₂N₄O₂, 374.44. m/z found, 375.2 [M+H]⁺. ¹H NMR(CDCl₃): 8.08 (d, J=5.7 Hz, 1H), 7.95-7.81 (m, 3H), 7.59-7.46 (m, 4H),6.04 (d, J=5.7 Hz, 1H), 4.13 (dd, J=12.8, 7.9 Hz, 1H), 4.00-3.80 (m,5H), 3.80-3.65 (m, 2H), 3.55-3.40 (m, 2H), 3.22-3.09 (m, 2H), 3.05-2.91(m, 1H).

Example 59:2-[(2-Ethoxyphenyl)carbonyl]-5-(4-methoxypyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared according to the procedure used forExample 15 utilizing2-(4-methoxy-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole and2-ethoxybenzoic acid. MS (ESI) mass calcd. for C₂₀H₂₄N₄O₃, 368.44. m/zfound, 369.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.07 (d, J=5.7 Hz, 1H), 7.37-7.28(m, 2H), 6.99 (t, J=7.4 Hz, 1H), 6.91 (d, J=8.3 Hz, 1H), 6.02 (d, J=5.7Hz, 1H), 4.07 (q, J=7.0 Hz, 2H), 4.01-3.85 (m, 5H), 3.84-3.70 (m, 2H),3.65-3.45 (m, 3H), 3.34-3.22 (m, 1H), 3.16-2.92 (m, 2H), 1.35 (t, J=6.8Hz, 3H).

Example 60:2-[(2-Methoxynaphthalen-1-yl)carbonyl]-5-(4-methoxypyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 32 and 2-methoxy-naphthalene-1-carboxylic acid.MS (ESI) mass calcd. for C₂₃H₂₄N₄O₃, 404.46. m/z found, 405.2 [M+H]⁺. ¹HNMR (rotamers observed) 8.12-8.00 (m, 1H), 7.88 (d, J=9.1 Hz, 1H), 7.80(t, J=7.8 Hz, 1H), 7.70 (d, J=8.4 Hz, 0.6H), 7.63 (d, J=8.4 Hz, 0.4H),7.49 (t, J=7.6 Hz, 0.6H), 7.45-7.23 (m, 3.4H), 6.06-5.97 (m, 1H),4.16-4.02 (m, 1H), 3.99-3.79 (m, 7H), 3.80-3.62 (m, 2H), 3.61-3.47 (m,1H), 3.41-3.28 (m, 1H), 3.25-3.06 (m, 2H), 2.98 (d, J=8.2 Hz, 2H).

Example 61:2-(Biphenyl-2-ylcarbonyl)-5-[4-(1H-pyrazol-4-yl)pyrimidin-2-yl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 17 and 2-chloro-4-(1H-pyrazol-3-yl)-pyrimidine.MS (ESI) mass calcd. for C₂₆H₂₄N₆O, 436.57. m/z found, 437.2 [M+H]⁺.

Example 62:2-[4-(1H-Pyrazol-4-yl)pyrimidin-2-yl]-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 37 and 2-chloro-4-(1H-pyrazol-3-yl)-pyrimidine.MS (ESI) mass calcd. for C₂₄H₂₂N₆OS, 442.54. m/z found, 443.1 [M+H]⁺.

Example 63:2-(3,6-Dimethylpyrazin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 37 and 3-chloro-2,5-dimethyl-pyrazine. MS (ESI)mass calcd. for C₂₃H₂₄N₄OS, 404.54. m/z found, 405.2 [M+H]⁺.

Example 64:2-(Biphenyl-2-ylcarbonyl)-5-(3,5-dimethylpyrazin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 17 and 2-chloro-3,5-dimethyl-pyrazine. MS (ESI)mass calcd. for C₂₅H₂₆N₄O, 398.50. m/z found, 399.2 [M+H]⁺.

Example 65:2-Methyl-3-{5-[(2-thiophen-2-ylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 37 and 2-chloro-3-methyl-quinoxaline. MS (ESI)mass calcd. for C₂₆H₂₄N₄OS, 440.56. m/z found, 441.1 [M+H]⁺. ¹H NMR(CDCl₃): rotamers observed 7.77 (d, J=7.9 Hz, 1H), 7.64 (d, J=7.9 Hz,1H), 7.51-7.40 (m, 2H), 7.40-7.25 (m, 4H), 7.20-7.14 (m, 2H), 6.93 (brs, 1H), 3.86-3.74 (m, 2H), 3.70-3.60 (br m, 1.3H), 3.58-3.40 (br m,1.6H), 3.26-3.10 (m, 1.7H), 2.95-2.82 (br m, 1.7H), 2.76 (br m, 1.5H),2.62 (s, 3H).

Example 66:2-[5-(Biphenyl-2-ylcarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-3-methylquinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 17 and 2-chloro-3-methyl-quinoxaline. MS (ESI)mass calcd. for C₂₈H₂₆N₄O, 434.53. m/z found, 435.1 [M+H]⁺. ¹H NMR(CDCl₃): 7.85-7.72 (m, 1H), 7.65 (br s, 1H), 7.53-7.30 (m, 9H), 7.21 (d,J=10.5 Hz, 2H), 3.80-3.54 (br m, 3.5H), 3.44-3.28 (br m, 1.5H),3.15-2.90 broad (m, 2.5H), 2.85-2.70 (br m, 1.5H), 2.65-2.50 (m, 4H).

Example 67:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-(1H-pyrazol-1-yl)phenyl]carbonyl}octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2-pyrazol-1-yl-benzoic acid. MS (ESI) masscalcd. for C₂₄H₂₄N₆O, 388.47. m/z found, 389.1 [M+H]⁺. ¹H NMR (CDCl₃):rotamers observed, 7.73 (broad d, J=1.9 Hz, 1H), 7.52 (broad d, J=7.9Hz, 1.6H), 7.48-7.39 (m, 1.3H), 7.38-7.29 (m, 2H), 6.31 (br s, 1H), 6.22(s, 1H), 3.75-3.64 (m, 2H), 3.46 (dd, J=12.7, 4.4 Hz, 1.4H), 3.38 broad(s, 7H), 3.27 (dd, J=11.7, 4.2 Hz, 1.3H), 3.10 (br s, 1H), 2.90-2.65 (m,3.3H), 2.23 (s, 6H).

Example 68:2-(4,6-Dimethoxypyrimidin-2-yl)-5-[(2-fluoro-6-pyrimidin-2-ylphenyl)carbonyl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 14 and Intermediate 39. MS (ESI) mass calcd. forC₂₃H₂₃FN₆O₃, 450.47. m/z found, 451.1 [M+H]⁺. ¹H NMR (CDCl₃): rotamersobserved, 8.75-8.65 (m, 2H), 8.12-8.01 (m, 1H), 7.45-7.38 (m, 1H),7.20-7.12 (m, 1H), 7.05 (t, J=4.9 Hz, 1H), 5.32 (s, 1H), 3.96-3.41 (m,12.4H), 3.32-2.27 (m, 0.7H), 3.22-3.15 (m, 0.5H), 3.06-2.86 (m, 2.4H).

Example 69:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(2-pyridin-2-ylphenyl)carbonyl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2-pyridin-2-yl-benzoic acid. MS (ESI) masscalcd. for C₂₄H₂₅N₅O, 399.49. m/z found, 400.1 [M+H]⁺.

Example 70:2-(4,6-Dimethoxypyrimidin-2-yl)-5-[(2-pyridin-2-ylphenyl)carbonyl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 39 and 2-pyridin-2-yl-benzoic acid. MS (ESI) masscalcd. for C₂₄H₂₅N₅O₃, 431.49. m/z found, 432.2 [M+H]⁺. ¹H NMR (CDCl₃):8.49 (d, J=3.9 Hz, 1H), 7.69-7.49 (m, 3H), 7.48-7.29 (m, 3H), 7.15-7.04(m, 1H), 5.32 (s, 1H), 3.92-3.61 (m, 8H), 3.60-3.40 (m, 2H), 3.35-3.15(m, 3H), 2.98-2.65 (m, 3H).

Example 71:2-(4,6-Dimethoxypyrimidin-2-yl)-5-[(5-fluoro-2-pyrimidin-2-ylphenyl)carbonyl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 39 and Intermediate 13. MS (ESI) mass calcd. forC₂₃H₂₃FN₆O₃, 450.18. m/z found, 451.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.68 (d,J=4.9 Hz, 2H), 8.25 (dd, J=8.7, 5.5 Hz, 1H), 7.28-7.15 (m, 2H), 7.12(dd, J=8.6, 2.5 Hz, 1H), 5.31 (s, 1H), 3.84-3.65 (m, 7H), 3.63-3.33 (m,5H), 3.13-2.86 (m, 4H).

Example 72:2-(4,6-Dimethoxypyrimidin-2-yl)-5-{[5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 39 and Intermediate 1. MS (ESI) mass calcd. forC₂₂H₂₂FN₇O₃, 439.18. m/z found, 440.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.89 (dd,J=8.9, 4.7 Hz, 1H), 7.66 (s, 1H), 7.25-7.01 (m, 2H), 5.32 (s, 1H), 3.77(m, 8H), 3.67-3.54 (m, 2H), 3.52-3.26 (m, 3H), 3.01-2.78 (m, 3H).

Example 73:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(2-fluoro-6-pyrimidin-2-ylphenyl)carbonyl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and Intermediate 14. MS (ESI) mass calcd. forC₂₃H₂₃FN₆O, 418.47. m/z found, 419.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.75-8.65(m, 2H), 8.10-7.96 (m, 1.2H), 7.40 (dd, J=13.8, 8.0 Hz, 1.2H), 7.24-7.08(m, 2.7H), 7.08-7.00 (m, 0.8H), 6.22 (s, 1H), 4.00-3.39 (m, 7H),3.34-3.14 (m, 1H), 3.01 (d, J=6.8 Hz, 2H), 2.23 (s, 6H).

Example 74:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(5-fluoro-2-pyrimidin-2-ylphenyl)carbonyl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and Intermediate 13. MS (ESI) mass calcd. forC₂₃H₂₃FN₆O, 418.47. m/z found, 419.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.81 (d,J=4.9 Hz, 2H), 8.36 (dd, J=8.8, 5.6 Hz, 1H), 7.44-7.14 (m, 3H), 6.44 (s,1H), 6.44 (s, 1H), 3.98-3.75 (m, 2H), 3.76-3.48 (m, 5H), 3.24-2.97 (m,3H), 2.32 (s, 6H).

Example 75:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and Intermediate 1. MS (ESI): mass calculatedfor C₂₁H₂₂FN₇O, 407.45, m/z found 408.2 [M+1]⁺. ¹H NMR (CDCl₃) 7.97-7.92(m, 1H), 7.73 (s, 2H), 7.23-7.06 (m, 2H), 6.30 (s, 1H), 3.90-3.80 (m,Hz, 2H), 3.72-3.55 (m, 5.9 Hz, 4H), 3.53-3.46 (m, Hz, 1H), 3.39 (br s,1H), 3.08-2.87 (m, 4H), 2.30 (s, 6H).

Example 76:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(2-ethylphenyl)carbonyl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2-ethylbenzoic acid. MS (ESI) mass calcd.for C₂₁H₂₆N₄O, 350.47. m/z found, 351.3 [M+H]⁺. ¹H NMR (CDCl₃):7.34-7.14 (m, 4H), 6.30 (s, 1H), 3.93 (m, 2H), 3.77 (dd, J=11.6, 7.3 Hz,1H), 3.64 (m, 2H), 3.51-3.41 (m, 2H), 3.16-3.02 (m, 2H), 3.01-2.90 (m,1H), 2.69-2.57 (m, 2H), 2.29 (s, 6H), 1.20 (t, J=7.6 Hz, 3H).

Example 77:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(2-ethoxynaphthalen-1-yl)carbonyl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2-ethoxy-naphthalene-1-carboxylic acid. MS(ESI) mass calcd. for C₂₅H₂₆N₄O₂, 416.53. m/z found, 417.2 [M+H]⁺.

Example 78:2-(4,6-Dimethoxypyrimidin-2-yl)-5-{[2-(1H-pyrazol-1-yl)phenyl]carbonyl}octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 39 and 2-pyrazol-1-yl-benzoic acid. MS (ESI) masscalcd. for C₂₂H₂₄N₆O₃, 420.46. m/z found, 421.1 [M+H]⁺. ¹H NMR (CDCl₃):7.74 (d, J=2.0 Hz, 1H), 7.59-7.29 (m, 5H), 6.31 (br s, 1H), 5.32 (s,1H), 3.90-3.64 (m, 7.8H), 3.61-3.41 (m, 2.2H), 3.40-3.05 (m, 3H),2.95-2.65 (m, 3H).

Example 79:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(5-phenyl-1,3-oxazol-4-yl)carbonyl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 5-phenyl-oxazole-4-carboxylic acid. MS(ESI) mass calcd. for C₂₂H₂₃N₅O₂, 389.46. m/z found, 390.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.91 (m, 2H), 7.86 (s, 1H), 7.46-7.33 (m, 3H), 6.28 (s,1H), 4.03-3.83 (m, 3H), 3.74 (m, 2H), 3.64-3.47 (m, 3H), 3.08-2.98 (m,2H), 2.29 (m, 6H).

Example 80:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(5-phenylisoxazol-4-yl)carbonyl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 5-phenyl-isoxazole-4-carboxylic acid. MS(ESI) mass calcd. for C₂₂H₂₃N₅O₂, 389.46. m/z found, 390.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.37 (s, 1H), 7.84-7.75 (m, 2H), 7.49-7.36 (m, 3H), 6.30(s, 1H), 4.00-3.80 (m, 2H), 3.73-3.62 (m, 2H), 3.59-3.42 (m, 2H), 3.36(dd, J=11.7, 4.5 Hz, 1H), 3.16-2.85 (m, 3H), 2.37-2.22 (s, 6H).

Example 81:[5-(2-Isopropyl-6-methyl-pyrimidin-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-[1,2,3]triazol-2-yl-phenyl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and 4-chloro-2-isopropyl-6-methyl-pyrimidine.MS (ESI): mass calculated for C₂₃H₂₇N₇O, 417.51, m/z found 418.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.99 (d, J=8.0 Hz, 1H), 7.73 (s, 2H), 7.59-7.38(m, 3H), 5.92 (s, 1H), 3.97-2.85 (m, 10H), 2.35 (s, 3H), 1.33-1.21 (m,6H).

Example 82:2-[(2-Bromophenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2-bromobenzoic acid. MS (ESI) mass calcd.for C₁₉H₂₁BrN₄O, 401.31. m/z found, 401.1, 403.1 [M+H]⁺.

Example 83:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and Intermediate 2. MS (ESI) mass calcd. forC₂₁H₂₃N₇O, 389.46. m/z found, 374.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.98 (d,J=8.1 Hz, 1H), 7.74 (br s, 2H), 7.55-7.48 (m, 1H), 7.42 (d, J=4.1 Hz,2H), 6.29 (s, 1H), 3.93-3.81 (m, 2H), 3.64 (m, 3H), 3.48 (dd, J=11.6,4.2 Hz, 1H), 3.36 (br s, 1H), 3.08-2.86 (m, 3H), 2.30 (s, 6H).

Example 84:2-(4,6-Dimethoxypyrimidin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and 2-chloro-4,6-dimethoxypyrimidine. MS (ESI)mass calcd. for C₂₁H₂₃N₇O₃, 421.46. m/z found, 422.2 [M+H]⁺. ¹H NMR(CDCl₃): 8.05-7.95 (m, 2H), 7.75 (br s, 1H), 7.57-7.48 (m, 1H),7.46-7.41 (m, 2H), 5.39 (s, 1H), 3.93-3.79 (m, 5H), 3.76-3.62 (m, 2H),3.56 (dd, J=11.8, 5.4 Hz, 1H), 3.49-3.33 (m, 2H), 2.96 (s, 3H), 2.89 (s,3H).

Example 85:2-[5-{[2-(4H-1,2,4-Triazol-3-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid.MS (ESI) mass calcd. for C₂₃H₂₁N₇O, 411.47. m/z found, 412.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.28 (s, 1H), 8.11 (d, J=8.1 Hz, 1H), 8.01 (br s, 1H), 7.89(dd, J=8.2, 1.2 Hz, 1H), 7.69 (dd, J=8.4, 1.0 Hz, 1H), 7.59 (ddd, J=8.4,7.0, 1.4 Hz, 1H), 7.55-7.43 (m, 2H), 7.42-7.33 (m, 2H), 3.89-4.00 (m,2H), 3.82-3.72 (m, 2H), 3.71-3.64 (m, 1H), 3.55-3.42 (m, 2H), 3.20-2.98(m, 3H).

Example 86:2-[5-{[2-(4H-1,2,4-Triazol-3-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-1,3-benzoxazole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 28 and 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid.MS (ESI) mass calcd. for C₂₂H₂₀N₆O₂, 400.43. m/z found, 401.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.15-8.02 (m 2H), 7.56-7.40 (m, 2H), 7.347-7.30 (m, 2H),7.29-7.23 (m, 1H), 7.17 (td, J=7.7, 1.1 Hz, 1H), 7.05-6.98 (m, 1H),3.98-3.42 (m, 7H), 3.26-2.93 (m, 3H).

Example 87:2-(4-Methylpyrimidin-2-yl)-5-{[2-(4H-1,2,4-triazol-3-yl)phenyl]carbonyl}octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 27 and 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid.MS (ESI) mass calcd. for C₂₀H₂₁N₇O, 375.55. m/z found, 376.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.18-8.04 (m, 3H), 7.55-7.42 (m, 2H), 7.39-7.33 (m, 1H),6.39 (d, J=5.0 Hz, 1H), 3.96-3.79 (m, 2H), 3.77-3.63 (m, 2H), 3.62-3.55(m, 1H), 3.46-3.37 (m, 2H), 3.15-3.06 (m, 1H), 3.05-2.98 (m, 1H),2.95-2.90 (m, 1H), 2.33 (s, 3H).

Example 88:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(2-ethoxyphenyl)carbonyl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2-ethoxybenzoic acid. MS (ESI) mass calcd.for C₂₁H₂₆N₄O₂, 366.46. m/z found, 367.2 [M+H]⁺. ¹H NMR (CDCl₃):7.37-7.21 (m, 2H), 7.03-6.91 (m, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.26 (d,J=20.0 Hz, 1H), 4.04 (q, J=7.0 Hz, 2H), 3.95-3.85 (m, 2H), 3.76 (dd,J=11.5, 7.3 Hz, 1H), 3.69-3.59 (m, 2H), 3.57-3.45 (m, 2H), 3.29-3.20 (m,1H), 3.12-2.89 (m, 2H), 2.29 (s, 6H), 1.33 (t, J=7.0 Hz, 3H).

Example 89:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[4-fluoro-2-(trifluoromethyl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2-trifluoromethyl-4-fluorobenzoic acid. MS(ESI) mass calcd. for C₂₀H₂₀F₄N₄O, 408.4. m/z found, 409.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.46-7.27 (m, 3H), 6.37-6.25 (m, 1H), 4.01-3.87 (m, 2H),3.82-3.76 (m 1H), 3.67-3.57 (m, 2H), 3.53-3.38 (m, 2H), 3.14-3.04 (m,2H), 3.04-2.96 m, 1H), 2.31 (s 6H).

Example 90:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(4-fluoronaphthalen-1-yl)carbonyl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 4-fluoro-naphthalene-1-carboxylic acid. MS(ESI) mass calcd. for C₂₃H₂₃FN₄O, 390.45. m/z found, 391.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.16-8.10 (m 1H), 7.92-7.82 (m, 1H), 7.63-7.53 (m, 2H),7.403-7.36 (m, 1H), 7.14 (dd, J=10.2, 7.8 Hz, 1H), 6.31 (s, 1H),4.14-4.06 (m, 1H), 3.95-3.89 (m, 1H), 3.84-3.63 (m, 3H), 3.50-3.37 (m,2H), 3.17-3.08 (m, 2H), 2.98-2.90 (m, 1H), 2.30 (s, 6H).

Example 91:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-(1-methylethyl)phenyl]carbonyl}octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2-isopropyl-benzoic acid. MS (ESI) masscalcd. for C₂₂H₂₈N₄O, 364.48. m/z found, 365.3 [M+H]⁺. ¹H NMR (CDCl₃):7.37-7.30 (m, 2H), 7.23-7.10 (m, 2H), 6.30 (s, 1H), 4.00-3.86 (m, 2H),3.79-3.73 (m, 1H), 3.71-3.58 (m, 2H), 3.51-3.40 (m, 2H), 3.19-2.89 (m,4H), 2.30 (s, 6H), 1.29-1.17 (m, 6H).

Example 92:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(3-methoxy-2-methylphenyl)carbonyl]octahydro-pyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 3-methoxy-2-methyl-benzoic acid. MS (ESI)mass calcd. for C₂₁H₂₆N₄O₂, 366.47. m/z found, 367.2 [M+H]⁺. ¹H NMR(CDCl₃): 7.19 (dd, J=14.3, 6.5 Hz, 1H), 6.81 (dd, J=14.3, 7.8 Hz, 2H),6.30 (s, 1H), 4.01-3.85 (m, 2H), 3.83 (s, 3H), 3.77 (dd, J=11.6, 7.3 Hz,1H), 3.69-3.58 (m, 2H), 3.50-3.39 (m, 2H), 3.15-3.00 (m, 2H), 3.00-2.90(m, 1H), 2.30 (s, 6H), 2.14 (s, 3H).

Example 93:2-(4,6-Dimethylpyrimidin-2-yl)-5-(naphthalen-1-ylcarbonyl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and naphthalene-1-carboxylic acid. MS (ESI)mass calcd. for C₂₃H₂₄N₄O, 372.46. m/z found, 373.2 [M+H]⁺. ¹H NMR(CDCl₃): 7.91-7.79 (m, 3H), 7.54-7.40 (m, 4H), 6.30 (s, 1H), 4.11 (dd,J=12.8, 7.9 Hz, 1H), 3.92 (dd, J=11.6, 7.6 Hz, 1H), 3.80 (dd, J=12.8,4.9 Hz, 1H), 3.75-3.64 (m, 2H), 3.49-3.36 (m, 2H), 3.17-3.06 (m, 2H),2.97-2.87 (m, 1H), 2.31 (s, 6H).

Example 94:2-[5-{[2-(4H-1,2,4-Triazol-3-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-3-(trifluoromethyl)quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 30 and 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid.MS (ESI) mass calcd. for C₂₄H₂₀F₄N₇O, 479.47. m/z found, 480.2 [M+H]⁺.¹H NMR (CDCl₃): 8.12-7.93 (m, 3H), 7.77 (dd, J=8.5, 0.9 Hz, 1H), 7.69(ddd, J=8.4, 6.8, 1.4 Hz, 1H), 7.52-7.41 (m, 3H), 7.38-7.34 (m, 1H),4.01-3.79 (m, 3H), 3.78-3.66 (m, 2H), 3.49 (dd, J=23.0, 15.0 Hz, 2H),3.16-2.88 (m, 3H).

Example 95:2-Methyl-3-[5-{[2-(4H-1,2,4-triazol-3-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 29 and 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid.MS (ESI) mass calcd. for C₂₄H₂₃N₇O, 425.49. m/z found, 426.3 [M+H]⁺. ¹HNMR (CDCl₃): 8.13 (d, J=7.3 Hz, 1H), 8.01 (s, 1H), 7.83 (dd, J=8.2, 1.1Hz, 1H), 7.72 (dd, J=8.3, 1.0 Hz, 1H), 7.59-7.35 (m, 5H), 4.00-3.65 (m,5H), 3.47 (s, 2H), 3.22-2.89 (m, 3H), 2.70 (s, 3H).

Example 96:2-[6-Methyl-2-(trifluoromethyl)pyrimidin-4-yl]-5-{[2-(4H-1,2,4-triazol-3-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 31 and 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid.MS (ESI) mass calcd. for C₂₁H₂₀F₃N₇O, 443.43. m/z found, 444.2 [M+H]⁺.¹H NMR (CDCl₃): 8.11-7.99 (m, 2H), 7.55-7.42 (m, 2H), 7.37-7.29 (m, 1H),6.17 (br s, 1H), 3.92-3.39 (m, 7H), 3.15-2.90 (m 3H), 2.42 (s, 3H).

Example 97:2-[6-Methyl-2-(trifluoromethyl)pyrimidin-4-yl]-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 31 and Intermediate 2. MS (ESI) mass calcd. forC₂₁H₂₀F₃N₇O, 443.43. m/z found, 444.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.99 (d,J=8.0 Hz, 1H), 7.74 (s, 2H), 7.58-7.49 (m, 1H), 7.48-7.38 (m, 2H), 6.22(br s, 1H), 4.05-3.33 (m, 7H), 3.24-2.91 (m, 3H), 2.45 (s, 3H).

Example 98:2-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-[6-methyl-2-(trifluoromethyl)pyrimidin-4-yl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 31 and Intermediate 12. MS (ESI) mass calcd. forC₂₁H₁₉F₄N₇O, 461.42. m/z found, 462.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.91-7.78(m, 2H), 7.72 (s, 1H), 7.54-7.43 (m, 1H), 7.20-7.10 (m, 1H), 6.30-6.20(br m, 1H), 4.07-3.52 (m, 6H), 3.42-3.02 (m, 4H), 2.47 (d, J=19.9 Hz,3H).

Example 99:2-{[4-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-[6-methyl-2-(trifluoromethyl)pyrimidin-4-yl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 31 and Intermediate 4. MS (ESI) mass calcd. forC₂₁H₁₉F₄N₇O, 461.42. m/z found, 462.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.76 (brs, 3H), 7.47-7.36 (m, 1H), 7.19-7.09 (m, 1H), 6.22 (br s, 1H), 4.05-3.32(m, 7H), 2.98 (dd, J=40.7, 34.8 Hz, 3H), 2.44 (s, 3H).

Example 100:2-(6-Methylpyrazin-2-yl)-5-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 8 and 2-chloro-6-methyl-pyrazine. MS (ESI): masscalculated for C₂₁H₂₃N₇O, 389.46. m/z found 390.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 7.87-7.81 (m, 1H), 7.75-7.53 (m, 4H), 7.35-7.29 (m, 1H),7.24-7.18 (m, 1H), 3.94-3.83 (m, 1H), 3.80-3.66 (m, 2H), 3.64-3.54 (m,1H), 3.50-3.30 (m, 3H), 3.12-2.90 (m, 3H), 2.41 (s, 2H), 2.38 (s, 3H).

Example 101:2-(3,6-Dimethylpyrazin-2-yl)-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 34 and Intermediate 12. MS (ESI): mass calculatedfor C₂₁H₂₂FN₇O, 407.45. m/z found 408.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.90-7.80 (m, 2H), 7.78-7.71 (m, 2H), 7.54-7.44 (m, 1H), 7.20-7.12 (m,1H), 3.97-3.90 (m, 1H), 3.86-3.40 (m, 6H), 3.32-3.22 (m, 1H), 3.13-2.91(m, 2H), 2.55-2.49 (m, 3H), 2.39-2.33 (m, 3H).

Example 102:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(5-methyl-2-pyrimidin-2-ylphenyl)carbonyl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 5-methyl-2-pyrimidin-2-yl-benzoic acid. MS(ESI): mass calculated for C₂₄H₂₆N₆O, 414.51. m/z found 415.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): 8.74 (d, J=4.9, 2H), 8.20 (d, J=8.1, 1H),7.34-7.28 (m, 1H), 7.17-7.15 (m, 1H), 7.10-7.03 (m, 1H), 6.29 (s, 1H),3.95-3.79 (m, 2H), 3.76-3.61 (m, 3H), 3.59-3.40 (m, 2H), 3.18-3.10 (m,1H), 3.09-2.87 (m, 2H), 2.41 (s, 3H), 2.30 (s, 6H).

Example 103:2-(3,6-Dimethylpyrazin-2-yl)-5-[(5-methyl-2-pyrimidin-2-ylphenyl)carbonyl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 34 and 5-methyl-2-pyrimidin-2-yl-benzoic acid. MS(ESI): mass calculated for C₂₄H₂₆N₆O, 414.51. m/z found 415.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): 8.77 (d, J=4.9, 2H), 8.22 (d, J=8.1, 1H), 7.73 (s,1H), 7.34-7.29 (m, 1H), 7.21-7.16 (m, 1H), 7.11 (t, J=4.8, 1H),3.96-3.89 (m, 1H), 3.86-3.79 (m, 1H), 3.74-3.61 (m, 2H), 3.57-3.51 (m,1H), 3.49-3.38 (m, 2H), 3.18-3.12 (m, 1H), 3.08-2.98 (m, 1H), 2.96-2.86(m, 1H), 2.50 (s, 3H), 2.42 (s, 3H), 2.36 (s, 3H).

Example 104:2-(3,6-Dimethylpyrazin-2-yl)-5-{[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 34 and Intermediate 4. MS (ESI): mass calculatedfor C₂₁H₂₂FN₇O, 407.45. m/z found 408.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃)7.83-7.72 (m, 4H), 7.42 (dd, J=8.5, 5.8, 1H), 7.14 (ddd, J=8.5, 7.8,2.5, 1H), 3.94-3.86 (m, 1H), 3.82-3.74 (m, 1H), 3.73-3.60 (m, 2H),3.56-3.47 (m, 1H), 3.42-3.31 (m, 2H), 3.10-2.82 (m, 3H), 2.50 (s, 3H),2.36 (s, 3H).

Example 105:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[5-iodo-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and Intermediate 12. MS (ESI): mass calculatedfor C₂₁H₂₂IN₇O, 515.36. m/z found 516.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.87-7.80 (m, 1H), 7.79-7.67 (m, 4H), 6.30 (s, 1H), 3.94-3.82 (m, 2H),3.74-3.56 (m, 3H), 3.53-3.30 (m, 2H), 3.13-2.85 (m, 3H), 2.29 (s, 6H).

Example 106:4-[5-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-N,N-dimethyl-6-(trifluoromethyl)pyrimidin-2-amine

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 36 and Intermediate 12. MS (ESI): mass calculatedfor C₂₂H₂₂F₄N₈O, 490.47. m/z found 491.0 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 7.89-7.64 (m, 3H), 7.56-7.44 (m, 1H), 7.19-7.10 (m, 1H),6.01-5.74 (m, 1H), 4.10-2.86 (m, 16H).

Example 107:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone

Method A:

[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone.To a 3-necked, 3 L, round-bottomed flask equipped with a nitrogen line,temperature probe, heating mantle, reflux condenser, mechanical stirrer,and 1 N aq. NaOH scrubber were added2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 12, 120.98 g,75 wt %, 90.74 g actual, 438 mmol) and toluene (1 L). The mixture waswarmed to 50° C. for 1 h with stirring. The mixture was then cooled to25° C. and thionyl chloride (47.9 mL, 657 mmol) was added. The mixturewas warmed back to 50° C. and held for 1 h. During this time, in aseparate 5 L jacketed reactor equipped with a mechanical stirrer andtemperature probe were added toluene (600 mL), aqueous sodium carbonate(185.7 g, 1.75 mol in 1.6 L water), and2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole·HOAc(Intermediate 23, 122 g, 438 mmol). This biphasic mixture was cooled to0° C. After cooling to 0° C., the original slurry was poured through afilter and over the stirring biphasic mixture of amine and aqueoussodium carbonate. The mixture was allowed to warm to room temperature.After 2 h, additional2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole·HOAc (4g, 14 mmol) was added and the mixture was stirred for 30 additionalminutes. At the end of this period, the layers were separated and 100 mLof methanol were added to the organic layer. The organic layer was driedover MgSO₄, filtered, and concentrated to a white solid. This solid wastaken up in ethanol (1.4 L) and warmed to 77° C. The mixture was thencooled to 55° C. and seeded with previously crystallized material.(Note: The seeds were generated from slurrying the initial product in2-propanol at room temperature [100 mg/mL]). The mixture was cooled toroom temperature at a rate of 5° C. per hour. After stirring at roomtemperature for 14 h, the mixture was filtered and dried to provide thefinal product as a white crystalline solid (136.84 g, 74%). ¹H NMR (400MHz, CDCl₃): 7.88-7.78 (m, 1.78H), 7.75-7.69 (s, 1.22H), 7.51-7.43 (m,1H), 7.17-7.11 (m, 1H), 6.30-6.28 (m, 1H), 4.03-3.48 (m, 7H), 3.29-3.21(m, 1H), 3.15-2.92 (m, 2H), 2.30 (s, 6H). MS (ESI) mass calcd forC₂₁H₂₂FN₇O, 407.19. m/z found, 408 [M+H]⁺. Anal. calcd. for C₂₁H₂₂FN₇OC,61.90, H, 5.44, N, 24.06; found C, 61.83, H, 5.42, N, 24.08.

Method B:

Step A: A one-piece EasyMax reactor was equipped with a mechanicalstirred, a temperature probe, a reflux condenser and an NaOH scrubber.To the reactor was added 2-fluoro-6-triazol-2-yl benzoic acid (15.01 g,72.5 mmol) and toluene (150.0 g), N,N-dimethylformamide (0.06 g, 0.26mmol) was then added, the reaction was held at 20° C. prior to theaddition of thionyl chloride (11.31 g, 94.1 mmol) via syringe pump. Thereaction mixture was then heated to 50° C. over 15 minutes and then wasstirred at that temperature for 1.5 hours. The mixture was then heatedto 55° C. and 20.4 g of solvent were distilled in vacuo to give 139.4 gof acid chloride solution which was used as is in Step C below.

Step B. In a 500 mL jacketed reactor equipped with a mechanical stirrer,thermometer and reflux condenser was charged with2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole, bis-HClsalt (21.01 g, 72.1 mmol) and toluene (60.1 g) and the slurry wasstirred at 0° C. Sodium carbonate (30.6 g, 288.7 mmol) was thenseparately dissolved in water (151.5 g) and then added to the slurryover 15 minutes to give the crude amine solution which was used directlyin Step C.

Step C. To the crude amine solution from Step B in a 500 mL reactor heldat 0° C. was added the crude acid chloride solution from Step 1 and thereaction was held at 0° C. for another 15 minutes, then heated to 30° C.over 30 minutes. During this time the product started to precipitate andthe aqueous layer formed a slurry. The reaction was then cooled to 20°C. over 30 minutes and stirred at this temperature overnight. Themixture was then heated to 75° C. over 40 minutes and stirred for 35minutes. Stirring was then stopped and after 30 minutes the aqueouslayer was removed. To the organic layer was then added water (90.0 g)and the mixture was stirred for 20 minutes at 75° C., then the stirrerwas again stopped. After 10 minutes the aqueous layer was removed. Tothe remaining organic layer was added water (90.0 g) and the mixture wasagain stirred at 75° C. for 15 minutes, before the stirrer was againstopped, and after 10 minutes the aqueous layer was again removed.Distillation of the remaining toluene solution was then performed (at75° C., 350 mbar) to remove 70 mL of solvent. The remaining solution wasthen cooled to 50° C., and stirred for 20 minutes prior to the additionof Example 107 (0.04 g, seed crystals to start the crystallization). Thereaction was then stirred at 50° C. for 1.5 hour, then the thinsuspension was cooled to 30° C. over 1 hour then cooled to 0° C. over 1hour. After 90 minutes the product was isolated by suction filtration,the filter cake was washed with cyclohexane (75 g), then washed withwater (85.0 g) and the wet product cake was dried in vacuo at 55° C.overnight to give the title compound (25.21 g, 83%), Purity was assessedby HPLC (99.3%, 99.6%, and 99.3 area % (at 254, 235, and 280 nm,respectively).

Step D: The product of Step C (20.0 g, 48.9 mmol) was added to aone-piece EasyMax reactor and activated charcoal (Norit CN1, 2.00 g),ethanol (120.0 g) and 2-propanol (20.0 g) were then added. The mixturewas heated to 85° C. over 30 minutes, then stirred for 45 minutes, thencooled to 75° C. over 15 minutes. The mixture was then filtered via aglass fiber filter, the filter was washed with 2-propanol (20.0 g) thatwas previously heated to 70° C., The filtrates were then placed into a500 mL jacketed reactor equipped with a mechanical stirrer, refluxcondenser and thermometer and heated to 85° C., stirred for 5 minutes,cooled to 55° C. over 20 minutes and after 10 minutes at 55° C. asuspension of Example 107 (0.02 g) in 2-propanol (0.20 g) was added. Theresulting thin suspension was stirred at 55° C. for 1 hour, then wascooled to 45 over 1 hour and stirred for 30 minutes before it was cooledto 0° C. over 3 hours and was stirred at that temperature overnight.After 13 hours, the product was isolated by suction filtration, thefilter cake was washed via the reactor with 2-propanol (40.0 g, at 10°C.) to provide the wet product cake which was dried in vacuo at 60° C.overnight to give the title compound (18.18 g, 91.3%) as a white tooff-white crystalline solid. Purity was assessed by HPLC (99.7%, 99.8%,and 99.6 area % (at 254, 235, and 280 nm, respectively). Assays forresidual solvents showed the following: ethanol 1089 ppm, 2-propanol 348ppm, toluene 202 ppm, cyclohexane<20 ppm.

Example 108:N,N-Dimethyl-4-{5-[(5-methyl-2-pyrimidin-2-ylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-6-(trifluoromethyl)pyrimidin-2-amine

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 36 and 5-methyl-2-pyrimidin-2-yl-benzoic acid. MS(ESI): mass calculated for C₂₅H₂₆F₃N₇O, 497.53. m/z found 498.0 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.67 (dd, J=20.0, 4.9, 2H), 8.20 (d, J=10.1,1H), 7.34-7.30 (m, 1H), 7.19-7.15 (m, 1H), 7.13-7.03 (m, 1H), 5.85 (brs, 1H), 3.98-2.83 (m, 16H), 2.42 (s, 3H).

Example 109:4-{5-[(5-Fluoro-2-pyrimidin-2-ylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-N,N-dimethyl-6-(trifluoromethyl)pyrimidin-2-amine

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 36 and Intermediate 13. MS (ESI): mass calculatedfor C₂₄H₂₃F₄N₇O, 501.49. m/z found 502.0 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 8.70 (d, J=4.9, 2H), 8.38-8.31 (m, 1H), 7.24-7.17 (m, 1H),7.14-7.02 (m, 2H), 5.86 (br s, 1H), 4.06-2.78 (m, 16H).

Example 110:4-[5-{[5-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-N,N-dimethyl-6-(trifluoromethyl)pyrimidin-2-amine

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 36 and Intermediate 1. MS (ESI): mass calculatedfor C₂₂H₂₂F₄N₅O, 490.46. m/z found 490.9 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 8.00-7.92 (m, 1H), 7.78-7.64 (m, 2H), 7.26-7.20 (m, 1H),7.17-7.11 (m, 1H), 5.87 (br s, 1H), 3.96-2.87 (m, 16H).

Example 111:[5-(2-Dimethylamino-6-trifluoromethyl-pyrimidin-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(4-fluoro-2-[1,2,3]triazol-2-yl-phenyl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 36 and Intermediate 4. MS (ESI): mass calculatedfor C₂₂H₂₂F₄N₅O, 490.46. m/z found 490.9 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 7.84-7.64 (m, 3H), 7.45-7.36 (m, 1H), 7.20-7.07 (m, 1H), 5.87(br s, 1H), 4.04-2.79 (m, 16H).

Example 112:2-[(5-Methyl-2-pyrimidin-2-ylphenyl)carbonyl]-5-[6-methyl-2-(trifluoromethyl)pyrimidin-4-yl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 31 and 5-methyl-2-pyrimidin-2-yl-benzoic acid. MS(ESI): mass calculated for C₂₄H₂₃F₃N₆O, 468.48. m/z found 469.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.80-8.68 (m, 2H), 8.27-8.13 (m, 1H), 7.35-7.29(m, 1H), 7.20-7.03 (m, 2H), 6.31-6.04 (m, 1H), 4.15-2.80 (m, 10H),2.56-2.30 (m, 6H).

Example 113:2-[(5-Fluoro-2-pyrimidin-2-ylphenyl)carbonyl]-5-(4-phenylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 26 and Intermediate 13. MS (ESI): mass calculatedfor C₂₇H₂₃FN₆O, 466.52. m/z found 467.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):8.72-8.66 (m, 2H), 8.44-8.29 (m, 2H), 8.16-8.02 (m, 2H), 7.53-7.45 (m,3H), 7.21-7.14 (m, 1H), 7.10-7.06 (m, 1H), 7.01-6.98 (m, 1H), 6.87 (brs, 1H), 4.05-3.50 (m, 7H), 3.31-2.98 (m, 3H).

Example 114:2-{[5-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-[6-methyl-2-(trifluoromethyl)pyrimidin-4-yl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 21 and4-chloro-6-methyl-2-trifluoromethyl-pyrimidine. MS (ESI): masscalculated for C₂₁H₁₉F₄N₇O, 461.42. m/z found 462.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 8.04-7.87 (m, 1H), 7.81-7.63 (m, 1H), 7.29-7.18 (m, 1H),7.17-7.08 (m, 1H), 6.31-6.03 (m, 1H), 4.13-2.84 (m, 10H), 2.44 (s, 3H).

Example 115:[5-(2,6-Dimethyl-pyrimidin-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(5-fluoro-2-[1,2,3]triazol-2-yl-phenyl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 21 and 4-chloro-2,6-dimethyl-pyrimidine. MS(ESI): mass calculated for C₂₁H₂₂FN₇O, 407.45, m/z found 408.2 [M+H]⁺.¹H NMR (CDCl₃) 7.97 (dd, J=9.0, 4.8 Hz, 1H), 7.73 (s, 2H), 7.25-7.19 (m,1H), 7.16-7.10 (m, 1H), 5.94 (s, 1H), 3.95-2.88 (m, 10H), 2.50 (s, 3H),2.34 (s, 3H).

Example 116:4-{5-[(2-Fluoro-6-pyrimidin-2-ylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-N,N-dimethyl-6-(trifluoromethyl)pyrimidin-2-amine

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 36 and Intermediate 14. MS (ESI): mass calculatedfor C₂₄H₂₃F₄N₇O, 501.49. m/z found 502.0 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 8.86-8.63 (m, 2H), 8.22-8.05 (m, 1H), 7.56-7.40 (m, 1H),7.29-7.18 (m, 1H), 7.12 (br s, 1H), 6.03-5.73 (m, 1H), 4.19-2.90 (m,16H).

Example 117:2-[(2-Fluoro-6-pyrimidin-2-ylphenyl)carbonyl]-5-[6-methyl-2-(trifluoromethyl)pyrimidin-4-yl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 31 and Intermediate 14. MS (ESI): mass calculatedfor C₂₃H₂₀F₄N₆O, 472.45. m/z found 473.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 8.81-8.72 (m, 2H), 8.21-8.01 (m, 1H), 7.54-7.42 (m, 1H),7.27-7.20 (m, 1H), 7.18-7.10 (m, 1H), 6.36-6.04 (m, 1H), 4.19-2.93 (m,10H), 2.60-2.29 (m, 3H).

Example 118:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and Intermediate 1. MS (ESI): mass calculatedfor C₂₁H₂₂FN₇O, 408.45. m/z found 408.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.81-7.69 (m, 3H), 7.43-7.36 (m, 1H), 7.16-7.08 (m, 1H), 6.30 (s, 1H),3.93-3.81 (m, 2H), 3.75-3.56 (m, 3H), 3.52-3.30 (m, 2H), 3.10-2.87 (m,3H), 2.30 (s, 6H).

Example 119:N,N,6-Trimethyl-2-[5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]pyrimidin-4-amine

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and(2-chloro-6-methyl-pyrimidin-4-yl)-dimethyl-amine. MS (ESI): masscalculated for C₂₂H₂₆N₅O, 418.50. m/z found 419.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 8.02-7.94 (m, 1H), 7.75 (s, 2H), 7.56-7.46 (m, 1H),7.44-7.36 (m, 2H), 5.69 (s, 1H), 3.92-3.81 (m, 2H), 3.76-3.62 (m, 2H),3.60-3.52 (m, 1H), 3.50-3.42 (m, 1H), 3.40-3.29 (m, 1H), 3.04 (s, 6H),3.01-2.80 (m, 3H), 2.24 (s, 3H).

Example 120:N,N,4-Trimethyl-6-[5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]pyrimidin-2-amine

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and(4-chloro-6-methyl-pyrimidin-2-yl)-dimethyl-amine. MS (ESI): masscalculated for C₂₂H₂₆N₅O, 418.50. m/z found 419.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 8.01-7.95 (m, 1H), 7.80-7.65 (m, 2H), 7.57-7.48 (m, 1H),7.45-7.35 (m, 2H), 5.51-5.39 (m, 1H), 3.91-2.85 (m, 19H).

Example 121:N,N-Dimethyl-4-[5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6-(trifluoromethyl)pyrimidin-2-amine

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and(4-chloro-6-trifluoromethyl-pyrimidin-2-yl)-dimethyl-amine. MS (ESI):mass calculated for C₂₂H₂₃F₃N₅O, 472.47. m/z found 473.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃: 8.02-7.95 (m, 1H), 7.73 (s, 2H), 7.57-7.50 (m, 1H),7.46-7.39 (m, 2H), 5.97-5.75 (m, 1H), 3.99-2.80 (m, 16H).

Example 122:2-(2,6-Dimethylpyrimidin-4-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and 4-chloro-2,6-dimethyl-pyrimidine. MS(ESI): mass calculated for C₂₁H₂₃N₇O, 408.45. m/z found 389.46 [M+H]⁺.m/z found 390.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.01-7.95 (m, 1H), 7.74(s, 2H), 7.56-7.37 (m, 3H), 6.01-5.85 (m, 1H), 3.99-2.86 (m, 10H), 2.50(s, 3H), 2.34 (s, 3H).

Example 123:[5-(3,6-Dimethyl-pyrazin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(5-methyl-2-[1,2,3]triazol-2-yl-phenyl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 19 and 3-chloro-2,5-dimethyl-pyrazine. MS (ESI):mass calculated for C₂₂H₂₅N₇O, 413.49, m/z found 404.2 [M+H]⁺. ¹H NMR(CDCl₃) 7.85 (d, J=8.3 Hz, 1H), 7.78-7.70 (m, 3H), 7.35-7.29 (m, 1H),7.25-7.21 (m, 1H), 3.92-3.85 (m, 1H), 3.80-3.72 (m, 1H), 3.70-3.59 (m,2H), 3.53-3.47 (m, 1H), 3.45-3.23 (m, 1H), 3.04-2.78 (m, 4H), 2.50 (s,3H), 2.42 (s, 3H), 2.36 (s, 3H).

Example 124:2-[5-{[5-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-N,N,6-trimethylpyrimidin-4-amine

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 21 and(2-chloro-6-methyl-pyrimidin-4-yl)-dimethyl-amine. MS (ESI): masscalculated for C₂₂H₂₅FN₈O, 435.49. m/z found 437.3 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 7.99-7.93 (m, 1H), 7.73 (s, 2H), 7.23-7.18 (m, 1H),7.15-7.12 (m, 1H), 5.69 (s, 1H), 3.88-3.80 (m, 2H), 3.71-3.62 (m, 2H),3.59-3.52 (m, 1H), 3.49-3.32 (m, 2H), 3.15-2.83 (m, 9H), 2.24 (s, 3H).

Example 125:2-(5-Methoxypyridin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 37 and 2-chloro-5-methoxy-pyridine. MS (ESI):mass calculated for C₂₃H₂₃N₃O₂S, 405.52. m/z found 406.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.88 (d, J=2.7, 1H), 7.54-7.47 (m, 1H), 7.45-7.31 (m,4H), 7.25-7.19 (m, 1H), 7.18-7.12 (m, 1H), 7.06-6.88 (m, 1H), 6.30-6.13(m, 1H), 3.94-2.47 (m, 13H).

Example 126:2-[(2-Ethoxynaphthalen-1-yl)carbonyl]-5-(4-phenylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 26 and 2-ethoxy-naphthalene-1-carboxylic acid. MS(ESI): mass calculated for C₂₉H₂₆N₄O₂, 464.57. m/z found 465.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.42-8.33 (m, 1H), 8.14-7.98 (m, 2H), 7.89-7.61(m, 3H), 7.53-7.43 (m, 3H), 7.41-7.18 (m, 3H), 7.01-6.95 (m, 1H),4.31-2.91 (m, 12H), 1.49-1.23 (m, 3H).

Example 127:2-{[5-Methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(4-phenylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 19 and 2-chloro-4-phenyl-pyrimidine. MS (ESI):mass calculated for C₂₆H₂₅N₇O, 451.53. m/z found 452.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 8.43-8.32 (m, 1H), 8.15-7.99 (m, 2H), 7.88-7.80 (m,1H), 7.78-7.57 (m, 2H), 7.55-7.39 (m, 3H), 7.34-7.28 (m, 1H), 7.25-7.21(m, 1H), 7.01-6.96 (m, 1H), 4.09-2.87 (m, 10H), 2.41 (s, 3H).

Example 128:(4-Chloro-2-[1,2,3]triazol-2-yl-phenyl)-[5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 6 and 2-chloro-4,6-dimethylpyrimidine. MS (ESI):mass calculated for C₂₁H₂₂ClN₇O, 423.91. m/z found 424.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 8.03 (t, J=10.1 Hz, 1H), 7.76 (s, 2H), 7.41-7.29 (m,2H), 6.30 (s, 1H), 3.92-3.79 (m, 2H), 3.74-3.58 (m, 3H), 3.53-3.29 (m,2H), 3.10-2.86 (m, 3H), 2.30 (s, 6H).

Example 129:2-(4,6-Dimethoxypyrimidin-2-yl)-5-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 19 and 2-chloro-4,6-dimethoxypyrimidine. MS(ESI): mass calculated for C₂₂H₂₅N₇O₃, 435.49. m/z found 436.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.85 (d, J=8.3, 1H), 7.72 (s, 2H), 7.34-7.29(m, 1H), 7.24-7.21 (m, 1H), 5.39 (s, 1H), 3.99-3.60 (m, 10H), 3.57-3.27(m, 3H), 3.08-2.82 (m, 3H), 2.41 (s, 3H).

Example 130:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 19 and 2-chloro-4,6-dimethylpyrimidine. MS (ESI):mass calculated for C₂₂H₂₅N₇O, 403.49. m/z found 404.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.84 (d, J=8.3, 1H), 7.72 (br s, 2H), 7.33-7.29 (m,1H), 7.23-7.20 (m, 1H), 6.29 (s, 1H), 3.91-3.80 (m, 2H), 3.73-3.54 (m,3H), 3.50-3.24 (m, 2H), 3.07-2.81 (m, 3H), 2.40 (s, 3H), 2.29 (s, 6H).

Example 131:2-(4-Phenylpyrimidin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 26 and Intermediate 2. MS (ESI): mass calculatedfor C₂₅H₂₃N₇O, 437.50. m/z found 438.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):8.46-8.31 (m, 1H), 8.21-7.91 (m, 3H), 7.82-7.59 (m, 2H), 7.58-7.39 (m,6H), 7.01-6.97 (m, 1H), 4.04-3.31 (m, 7H), 3.17-2.86 (m, 3H).

Example 132:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[5-(2-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 18 and 2-chloro-4,6-dimethylpyrimidine. MS (ESI):mass calculated for C₂₃H₂₄FN₅OS, 437.54. m/z found 438.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.50-7.44 (m, 1H), 7.32-7.23 (m, 1H), 7.16-7.04 (m,2H), 6.29 (s, 1H), 3.93-3.80 (m, 2H), 3.76-3.67 (m, 2H), 3.61-3.54 (m,1H), 3.51-3.37 (m, 2H), 3.29-3.22 (m, 1H), 3.03-2.87 (m, 2H), 2.73 (s,3H), 2.30 (s, 6H).

Example 133:2-[(2-Thiophen-2-ylphenyl)carbonyl]-5-[6-(trifluoromethyl)pyridin-2-yl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 37 and 2-chloro-6-trifluoromethyl-pyridine. MS(ESI): mass calculated for C₂₃H₂₀F₃N₃OS, 443.49. m/z found 444.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.62-7.33 (m, 5H), 7.29-7.05 (m, 2H), 7.04-6.80(m, 2H), 6.37 (s, 1H), 4.01-2.47 (m, 10H).

Example 134:2-(6-Methylpyridin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 37 and 2-chloro-6-methyl-pyridine. MS (ESI): masscalculated for C₂₃H₂₃N₃OS, 389.52. m/z found 390.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 7.56-7.47 (m, 1H), 7.45-7.10 (m, 6H), 7.07-6.91 (m, 1H),6.43 (d, J=7.2, 1H), 6.04 (s, 1H), 3.96-2.57 (m, 10H), 2.38 (s, 3H).

Example 135:2-(4-Methylpyrimidin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and 2-chloro-4-methyl-pyrimidine. MS (ESI):mass calculated for C₂₀H₂₁N₇O, 375.43. m/z found 376.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 8.17 (d, J=5.0, 1H), 7.98 (d, J=8.1, 1H), 7.75 (s,2H), 7.56-7.48 (m, 1H), 7.44-7.40 (m, 2H), 6.40 (d, J=5.0, 1H),3.94-3.81 (m, 2H), 3.75-3.54 (m, 3H), 3.52-3.31 (m, 2H), 3.10-2.88 (m,3H), 2.35 (s, 3H).

Example 136:2-(4-Methylpyridin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 37 and 2-chloro-4-methyl-pyridine. MS (ESI): masscalculated for C₂₃H₂₃N₃OS, 389.52. m/z found 390.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 8.00 (d, J=5.2, 1H), 7.56-7.47 (m, 1H), 7.45-7.31 (m, 3H),7.25-7.11 (m, 2H), 7.09-6.90 (m, 1H), 6.42 (d, J=5.2, 1H), 6.06 (br s,1H), 3.98-2.59 (m, 10H), 2.27 (s, 3H).

Example 137:2-(6-Methoxypyridin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 37 and 2-chloro-6-methoxy-pyridine. MS (ESI):mass calculated for C₂₃H₂₃N₃O₂S, 405.52. m/z found 406.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.56-7.47 (m, 1H), 7.46-7.30 (m, 4H), 7.25-7.12 (m,2H), 7.09-6.90 (m, 1H), 6.01 (d, J=7.6, 1H), 5.77 (br s, 1H), 3.85 (s,3H), 3.71-2.59 (m, 10H).

Example 138:2-(4,6-Dimethoxypyrimidin-2-yl)-5-[(2-thiophen-2-ylphenyl)carbonyl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 37 and 2-chloro-4,6-dimethoxy-pyridine. MS (ESI):mass calculated for C₂₃H₂₄N₄O₃S, 436.54. m/z found 437.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.52 (d, J=7.5, 1H), 7.45-7.33 (m, 3H), 7.30-7.15 (m,2H), 7.00 (br s, 1H), 5.38 (s, 1H), 3.97-2.60 (m, 16H).

Example 139:2-{5-[(2-Thiophen-2-ylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1,3-benzoxazole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 37 and 2-chloro-benzooxazole. MS (ESI): masscalculated for C₂₄H₂₁N₃O₂S, 415.52. m/z found 416.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 7.83-6.68 (m, 11H), 4.20-2.47 (m, 10H).

Example 140:2-[(2-Thiophen-2-ylphenyl)carbonyl]-5-[3-(trifluoromethyl)pyridin-2-yl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 37 and 2-chloro-3-trifluoromethyl-pyridine. MS(ESI): mass calculated for C₂₃H₂₀F₃N₃OS, 443.49. m/z found 444.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.28 (dd, J=4.7, 1.4, 1H), 7.79 (dd, J=7.8,1.8, 1H), 7.55-7.49 (m, 1H), 7.46-7.33 (m, 3H), 7.30-7.19 (m, 2H), 7.01(br s, 1H), 6.71 (dd, J=7.7, 4.7, 1H), 3.98-2.54 (m, 10H).

Example 141:[5-(4-Phenyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-[2-(4H-[1,2,4]triazol-3-yl)-phenyl]-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 26 and 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid.MS (ESI): mass calculated for C₂₅H₂₃N₇O, 437.50. m/z found 438.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 12.43 (br s, 1H), 8.36 (d, J=5.2 Hz, 1H), 8.14(d, J=7.5 Hz, 1H), 8.08-7.91 (m, 3H), 7.60-7.42 (m, 5H), 7.39-7.31 (m,1H), 6.98 (t, J=6.1 Hz, 1H), 4.01-3.87 (m, 2H), 3.85-3.65 (m, 3H),3.61-3.40 (m, 2H), 3.28-2.89 (m, 3H).

Example 142:2-(4,6-Dimethoxypyrimidin-2-yl)-5-{[5-(2-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 18 and 2-chloro-4,6-dimethoxypyrimidine. MS(ESI): mass calculated for C₂₃H₂₄FN₅O₃S, 469.54. m/z found 470.0 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.47 (td, J=7.6, 1.7, 1H), 7.32-7.24 (m, 1H),7.17-7.11 (m, 1H), 7.10-7.03 (m, 1H), 5.39 (s, 1H), 3.94-3.78 (m, 8H),3.75-3.65 (m, 2H), 3.61 (dd, J=12.8, 4.3, 1H), 3.45-3.35 (m, 2H), 3.24(dd, J=11.4, 5.4, 1H), 3.02-2.85 (m, 2H), 2.72 (s, 3H).

Example 143:2-(4-Thiophen-2-ylpyrimidin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and 2-chloro-4-thiophen-2-yl-pyrimidine. MS(ESI): mass calculated for C₂₃H₂₁N₇OS, 443.53. m/z found 444.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.35-8.25 (m, 1H), 7.98 (d, J=8.1, 1H),7.80-7.63 (m, 3H), 7.56-7.38 (m, 4H), 7.18-7.09 (m, 1H), 6.85 (d, J=5.2,1H), 4.00-3.35 (m, 7H), 3.13-2.89 (m, 3H).

Example 144:2-[5-{[2-(2H-1,2,3-Triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-1,3-benzoxazole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and 2-chloro-benzooxazole. MS (ESI): masscalculated for C₂₂H₂₀N₆O₂, 400.44. m/z found 401.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 7.99 (d, J=8.1, 1H), 7.74 (s, 2H), 7.57-7.49 (m, 1H),7.46-7.40 (m, 2H), 7.40-7.36 (m, 1H), 7.30-7.25 (m, 1H), 7.21-7.15 (m,1H), 7.06-7.01 (m, 1H), 4.00-3.85 (m, 2H), 3.83-3.72 (m, 2H), 3.68-3.61(m, 1H), 3.59-3.41 (m, 2H), 3.19-2.97 (m, 3H).

Example 145:2-{5-[(2-Ethoxynaphthalen-1-yl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing 2-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-quinoxaline(Intermediate 35) and 2-ethoxy-naphthalene-1-carboxylic acid. MS (ESI):mass calculated for C₂₇H₂₆N₄O₂, 438.53. m/z found 439.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 8.32 (d, J=16.4, 1H), 7.95-7.55 (m, 6H), 7.52-7.17 (m,4H), 4.34-2.94 (m, 12H), 1.49-1.19 (m, 3H).

Example 146:2-{5-[(5-Fluoro-2-pyrimidin-2-ylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and Intermediate 13. MS (ESI): mass calculatedfor C₂₅H₂₁FN₆O, 440.48. m/z found 441.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):8.71 (d, J=4.9, 2H), 8.37-8.30 (m, 2H), 7.92-7.88 (m, 1H), 7.72-7.69 (m,1H), 7.63-7.57 (m, 1H), 7.43-7.37 (m, 1H), 7.23-7.17 (m, 1H), 7.11-7.05(m, 2H), 4.03-3.93 (m, 2H), 3.87-3.70 (m, 3H), 3.67-3.56 (m, 2H),3.26-3.03 (m, 3H).

Example 147:2-(6-Ethoxypyridin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and 2-chloro-6-ethoxypyridine. MS (ESI): masscalculated for C₂₂H₂₄N₆O₂, 404.47. m/z found 405.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 7.98 (d, J=8.1, 1H), 7.72 (s, 2H), 7.56-7.49 (m, 1H),7.46-7.33 (m, 3H), 6.00 (d, J=7.7, 1H), 5.83 (d, J=7.9, 1H), 4.33-4.23(m, 2H), 3.93-3.82 (m, 1H), 3.79-3.67 (m, 2H), 3.59-3.49 (m, 1H),3.47-3.33 (m, 2H), 3.32-3.25 (m, 1H), 3.11-2.86 (m, 3H), 1.38 (t, J=7.1,3H).

Example 148:2-[(5-Fluoro-2-pyrimidin-2-ylphenyl)carbonyl]-5-[4-(trifluoromethyl)pyrimidin-2-yl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 33 and Intermediate 13. MS (ESI): mass calculatedfor C₂₂H₁₈F₄N₆O, 459.42. m/z found 459.1 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 8.74 (d, J=4.9, 2H), 8.60-8.28 (m, 2H), 7.23-7.04 (m, 3H),6.84-6.75 (m, 1H), 4.03-2.97 (m, 10H).

Example 149:2-[5-{[2-(2H-1,2,3-Triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and 2-chloroquinoxaline. MS (ESI): masscalculated for C₂₃H₂₁N₇O, 411.47. m/z found 412.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 8.31 (s, 1H), 8.01-7.95 (m, 1H), 7.92-7.88 (m, 1H),7.79-7.65 (m, 3H), 7.62-7.32 (m, 5H), 4.01-3.35 (m, 7H), 3.22-2.98 (m,3H).

Example 150:2-[(5-Fluoro-2-pyrimidin-2-ylphenyl)carbonyl]-5-(4-methoxypyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 32 and Intermediate 13. MS (ESI): mass calculatedfor C₂₂H₂₁FN₆O₂, 420.45. m/z found 421.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 8.73 (d, J=4.9, 2H), 8.35 (dd, J=8.8, 5.6, 1H), 8.06 (d, J=5.7,1H), 7.23-7.02 (m, 3H), 6.01 (d, J=5.7, 1H), 4.01-3.43 (m, 10H),3.23-2.90 (m, 3H).

Example 151:2-(4-Furan-2-ylpyrimidin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and 2-chloro-4-furan-2-yl-pyrimidine. MS(ESI): mass calculated for C₂₃H₂₁N₇OS, 427.47. m/z found 428.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.37-8.30 (m, 1H), 7.98 (d, J=8.1, 1H),7.80-7.37 (m, 6H), 7.20-7.11 (m, 1H), 6.89 (d, J=5.1, 1H), 6.59-6.50 (m,1H), 3.99-3.30 (m, 7H), 3.12-2.91 (m, 3H).

Example 152:2-(5-Fluoropyridin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and 2,5-difluoropyridine. MS (ESI): masscalculated for C₂₀H₁₉FN₆O, 378.41. m/z found 379.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 8.03 (d, J=3.0, 1H), 7.99 (d, J=8.1, 1H), 7.73 (br s, 2H),7.58-7.37 (m, 3H), 7.30-7.18 (m, 1H), 6.26 (dd, J=9.1, 3.3, 1H),3.95-3.84 (m, 1H), 3.77-3.24 (m, 6H), 3.13-2.89 (m, 3H).

Example 153:2-{[2-(2H-1,2,3-Triazol-2-yl)phenyl]carbonyl}-5-[4-(trifluoromethyl)pyrimidin-2-yl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and 2-chloro-4-trifluoromethyl-pyrimidine. MS(ESI): mass calculated for C₂₀H₁₈F₃N₇O, 429.40. m/z found 430.1 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.58-8.40 (m, 1H), 7.99 (d, J=8.1, 1H), 7.75(br s, 2H), 7.56-7.48 (m, 1H), 7.45-7.39 (m, 2H), 6.80 (d, J=4.9, 1H),3.99-3.29 (m, 7H), 3.19-2.91 (m, 3H).

Example 154:2-(4-Methoxypyrimidin-2-yl)-5-{[2-(1H-1,2,4-triazol-5-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 32 and 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid.MS (ESI): mass calculated for C₂₀H₂₁N₇O, 391.44. m/z found 392.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.16-7.92 (m, 3H), 7.55-7.44 (m, 2H), 7.39-7.34(m, 1H), 6.00 (d, J=5.8, 1H), 4.02-3.33 (m, 10H), 3.20-2.83 (m, 4H).

Example 155:2-(3,6-Dimethylpyrazin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and 3-chloro-2,5-dimethyl-pyrazine. MS (ESI):mass calculated for C₂₀H₂₁NO₂, 391.44. m/z found 390.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 8.00 (d, J=8.1, 1H), 7.88-7.67 (m, 3H), 7.62-7.39 (m,3H), 3.90 (dd, J=12.6, 7.6, 1H), 3.77 (dd, J=10.7, 7.5, 1H), 3.72-3.60(m, 2H), 3.52 (dd, J=10.8, 5.1, 1H), 3.43-3.28 (m, 2H), 3.10-2.97 (m,2H), 2.95-2.85 (m, 1H), 2.51 (s, 3H), 2.36 (s, 3H).

Example 156:2-(4-Methoxypyrimidin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and 2-chloro-4-methoxypyrimidine. MS (ESI):mass calculated for C₂₀H₂₁N₇O₂, 391.43. m/z found 392.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 8.08-8.03 (m, 1H), 7.99 (d, J=8.1, 1H), 7.75 (s, 2H),7.57-7.48 (m, 1H), 7.44-7.41 (m, 2H), 6.00 (d, J=5.7, 1H), 3.97-3.79 (m,5H), 3.77-3.63 (m, 2H), 3.61-3.53 (m, 1H), 3.50-3.30 (m, 2H), 3.09-2.89,(m, 3H).

Example 157:2-{[5-Chloro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and Intermediate 9. MS (ESI): mass calculatedfor C₂₁H₂₂ClN₇O, 423.91. m/z found 424.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 7.95 (d, J=8.7, 1H), 7.74 (s, 2H), 7.48 (dd, J=8.7, 2.3, 1H),7.40 (d, J=2.3, 1H), 6.30 (s, 1H), 3.94-3.81 (m, 2H), 3.75-3.57 (m, 3H),3.55-3.29 (m, 2H), 3.11-2.78 (m, 3H), 2.30 (s, 6H).

Example 158:2-{[4-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(6-methylpyrazin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 22 and 2-chloro-6-methyl-pyrazine. MS (ESI): masscalculated for C₂₀H₂₀FN₇O, 393.43. m/z found 394.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 7.82-7.69 (m, 4H), 7.64 (s, 1H), 7.40 (dd, J=8.5, 5.8, 1H),7.17-7.10 (m, 1H), 3.97-3.83 (m, 1H), 3.81-3.68 (m, 2H), 3.65-3.55 (m,1H), 3.53-3.29 (m, 3H), 3.18-2.88 (m, 3H), 2.38 (s, 3H).

Example 159:2-{[4-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(4-methoxypyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 22 and 2-chloro-4-methoxypyrimidine. MS (ESI):mass calculated for C₂₀H₂₀FN₇O₂, 409.43. m/z found 388.3 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 8.06 (d, J=5.7, 1H), 7.88-7.62 (m, 3H), 7.45-7.37 (m,1H), 7.18-7.10 (m, 1H), 6.01 (d, J=5.7, 1H), 4.00-3.81 (m, 5H), 3.70(dd, J=20.4, 8.4, 2H), 3.62-3.53 (m, 1H), 3.51-3.28 (m, 2H), 3.13-2.84(m, 3H).

Example 160:2-(4,6-Dimethoxypyrimidin-2-yl)-5-{[4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 22 and 2-chloro-4,6-dimethoxypyrimidine. MS(ESI): mass calculated for C₂₁H₂₂FN₇O₃, 439.45. m/z found 440.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.86-7.66 (m, 3H), 7.47-7.34 (m, 1H), 7.17-7.06(m, 1H), 5.40 (s, 1H), 3.98-3.77 (m, 8H), 3.76-3.61 (m, 2H), 3.60-3.52(m, 1H), 3.50-3.29 (m, 2H), 3.09-2.84 (m, 3H).

Example 161:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(5-methoxy-2-[1,2,3]triazol-2-yl-phenyl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and Intermediate 10. MS (ESI): mass calculatedfor C₂₂H₂₅N₇O₂, 419.49. m/z found 420.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.85 (d, 1H), 7.74-7.64 (m, 2H), 7.07-6.99 (m, 1H), 6.94-6.88 (m, 1H),6.27 (s, J=20.0, 1H), 3.94-3.75 (m, 5H), 3.73-3.25 (m, 5H), 3.08-2.81(m, 3H), 2.32-2.27 (m, 6H).

Example 162:(2-Fluoro-6-[1,2,3]triazol-2-yl-phenyl)-[5-(4-methoxy-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 12 and 2-chloro-4-methoxypyrimidine. MS (ESI):mass calculated for C₂₀H₂₀FN₇O₂, 409.42. m/z found 410.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 8.10-8.01 (m, 1H), 7.92-7.78 (m, 2H), 7.73 (s, 1H),7.53-7.41 (m, 1H), 7.19-7.06 (m, 1H), 6.03-5.97 (m, 1H), 4.02-3.46 (m,10H), 3.33-3.20 (m, 1H), 3.16-2.88 (m, 2H).

Example 163:6-Chloro-2-{5-[(2,4-dimethoxyphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-1,3-benzothiazole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 40 and 2,4-dimethoxybenzoic acid. MS (ESI): masscalculated for C₂₂H₂₂ClN₃O₃S, 443.96. m/z found 444.2 [M+H]⁺.

Example 164:2-(Biphenyl-2-ylcarbonyl)-5-(4-phenylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 26 and biphenyl-2-carboxylic acid. MS (ESI) masscalcd. for C₂₉H₂₆N₄O, 446.56. m/z found, 447.3 [M+H]⁺.

Example 165:2-{5-[(2,6-Dimethoxyphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 2,6-dimethoxybenzoic acid. MS (ESI) masscalcd. for C₂₃H₂₄N₄O₃, 404.47. m/z found, 405.3 [M+H]⁺.

Example 166:2-[(2,6-Dimethoxyphenyl)carbonyl]-5-(4-phenylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 26 and 2,6-dimethoxybenzoic acid. MS (ESI) masscalcd. for C₂₅H₂₆N₄O₃, 430.51. m/z found, 431.2 [M+H]⁺.

Example 167:2-[(2,4-Dimethoxyphenyl)carbonyl]-5-(4-phenylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 26 and 2,4-dimethoxybenzoic acid. MS (ESI) masscalcd. for C₂₅H₂₆N₄O₃, 430.51. m/z found, 431.2 [M+H]⁺.

Example 168:2-[5-(Biphenyl-2-ylcarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]quinoxaline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and biphenyl-2-carboxylic acid. MS (ESI) masscalcd. for C₂₇H₂₄N₄O, 420.52. m/z found, 421.3 [M+H]⁺.

Example 169:2-[5-(Biphenyl-2-ylcarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-1,3-benzothiazole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 17 and 2-chloro-benzothiazole. MS (ESI) masscalcd. for C₂₆H₂₃N₃OS, 425.56. m/z found, 426.2 [M+H]⁺.

Example 170:2-{5-[(2,4-Dimethoxyphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-4-methylquinoline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 38 and 2-chloro-4-methyl-quinoline. MS (ESI) masscalcd. for C₂₅H₂₇N₃O₃, 417.51. m/z found, 418.3 [M+H]⁺.

Example 171:2-{5-[(2,4-Dimethoxyphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-6-methoxy-1,3-benzothiazole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 38 and 2-chloro-6-methoxy-benzothiazole. MS (ESI)mass calcd. for C₂₃H₂₅N₃O₄S, 439.54. m/z found, 440.2 [M+H]⁺.

Example 172:2-{5-[(2,4-Dimethoxyphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-6-methyl-1,3-benzothiazole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 38 and 2-chloro-6-methyl-benzothiazole. MS (ESI)mass calcd. for C₂₃H₂₅N₃O₃S, 423.54. m/z found, 424.2 [M+H]⁺.

Example 173:2-(Biphenyl-2-ylcarbonyl)-5-(6-methylpyridin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 17 and 2-chloro-6-methyl-pyridine. MS (ESI) masscalcd. for C₂₅H₂₅N₄₃O, 383.5. m/z found, 384.3 [M+H]⁺.

Example 174:2-(Biphenyl-2-ylcarbonyl)-5-(4-methylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 17 and 2-chloro-4-methyl-pyrimidine. MS (ESI)mass calcd. for C₂₄H₂₄N₄O, 384.49. m/z found, 385.2 [M+H]⁺.

Example 175:2-[5-(Biphenyl-2-ylcarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]quinoline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 17 and 2-chloro-quinoline. MS (ESI) mass calcd.for C₂₈H₂₅N₃O, 419.53. m/z found, 420.3 [M+H]⁺.

Example 176:2-[5-(Biphenyl-2-ylcarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6-fluoro-1,3-benzothiazole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 17 and 2-chloro-6-fluoro-benzothiazole. MS (ESI)mass calcd. for C₂₆H₂₂FN₃OS, 443.55. m/z found, 444.2 [M+H]⁺.

Example 177:2-(Biphenyl-2-ylcarbonyl)-5-(4-methoxypyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 17 and 2-chloro-4-methoxypyrimidine. MS (ESI)mass calcd. for C₂₄H₂₄N₄O₂, 400.48. m/z found, 401.2 [M+H]⁺.

Example 178:2-[5-(Biphenyl-2-ylcarbonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4-methylquinoline

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 17 and 2-chloro-4-methyl-quinoline. MS (ESI) masscalcd. for C₂₉H₂₇N₃O, 433.56. m/z found, 434.3 [M+H]⁺.

Example 179:(2,4-Dimethoxy-phenyl)-[5-(4-methoxy-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 38 and 2-chloro-4-methoxypyrimidine. MS (ESI):mass calculated for C₂₀H₂₄N₄O₄, 384.43. m/z found 385.2 [M+H]⁺.

Example 180:(5-Benzooxazol-2-yl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(2-methoxy-phenyl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 28 and 2-methoxybenzoic acid. MS (ESI): masscalculated for C₂₁H₂₁N₃O₃, 363.42. m/z found 364.2 [M+H]⁺.

Example 181:(2-Pyridin-3-yl-phenyl)-(5-quinoxalin-2-yl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 2-pyridin-3-yl-benzoic acid. MS (ESI):mass calculated for C₂₆H₂₃N₅O, 421.51. m/z found 422.3 [M+H]⁺.

Example 182:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-[2-(1H-imidazol-2-yl)-phenyl]-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2-(1H-imidazol-2-yl)-benzoic acid. MS(ESI) mass calcd. for C₂₂H₂₄N₆O, 388.47. m/z found, 398.2 [M+H]⁺.

Example 183:(5-Benzooxazol-2-yl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(2,4-dimethoxy-phenyl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 28 and 2,4-dimethoxybenzoic acid. MS (ESI): masscalculated for C₂₂H₂₃N₃O₄, 393.45. m/z found 394.2 [M+H]⁺.

Example 184:(5-Benzooxazol-2-yl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-biphenyl-2-yl-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 17 and 2-chloro-benzooxazole. MS (ESI): masscalculated for C₂₆H₂₃N₃O₂, 409.49. m/z found 410.2 [M+H]⁺.

Example 185:(2,4-Dimethoxy-phenyl)-[5-(6-methyl-pyridin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 38 and 2-chloro-6-methyl-pyridine. MS (ESI): masscalculated for C₂₁H₂₅N₃O₃, 367.45. m/z found 368.3 [M+H]⁺.

Example 186:(2,4-Dimethoxy-phenyl)-[5-(4-methyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 38 and 2-chloro-4-methylpyrimidine. MS (ESI):mass calculated for C₂₀H₂₄FN₄O₃, 368.43. m/z found 369.3 [M+H]⁺.

Example 187:Biphenyl-2-yl-[5-(6-methoxy-benzothiazol-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 17 and 2-chloro-6-methoxy-benzothiazole. MS(ESI): mass calculated for C₂₇H₂₅N₃O₂S, 455.57. m/z found 456.2 [M+H]⁺.

Example 188:Biphenyl-2-yl-[5-(6-methyl-benzothiazol-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 17 and 2-chloro-6-methyl-benzothiazole. MS (ESI):mass calculated for C₂₇H₂₅N₃OS, 439.57. m/z found 440.2 [M+H]⁺.

Example 189:[5-(6-Chloro-benzothiazol-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2,6-dimethoxy-phenyl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 40 and 2,6-dimethoxybenzoic acid. MS (ESI): masscalculated for C₂₂H₂₂ClN₃O₃S, 443.96. m/z found 444.2 [M+H]⁺.

Example 190:Biphenyl-2-yl-[5-(6-chloro-benzothiazol-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 40 and biphenyl-2-carboxylic acid. MS (ESI): masscalculated for C₂₆H₂₂ClN₃O₃S, 459.99. m/z found 460.2 [M+H]⁺.

Example 191:(2,4-Dimethoxy-phenyl)-(5-quinoxalin-2-yl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 2,4-dimethoxybenzoic acid. MS (ESI): masscalculated for C₂₃H₂₄N₄O₃, 404.47. m/z found 405.3 [M+H]⁺.

Example 192:(5-Benzooxazol-2-yl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(2,6-dimethoxy-phenyl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 41 and 2-chloro-benzooxazole. MS (ESI): masscalculated for C₂₂H₂₃N₃O₄, 393.45. m/z found 394.2 [M+H]⁺.

Example 193:(4′-Methyl-biphenyl-2-yl)-(5-quinoxalin-2-yl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 4′-methyl-biphenyl-2-carboxylic acid. MS(ESI): mass calculated for C₂₈H₂₆N₄O, 434.55. m/z found 435.3 [M+H]⁺.

Example 194:(5-Quinoxalin-2-yl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-(4′-trifluoromethyl-biphenyl-2-yl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 4′-trifluoromethyl-biphenyl-2-carboxylicacid. MS (ESI): mass calculated for C₂₈H₂₃F₃N₄O, 488.50. m/z found 489.2[M+H]⁺.

Example 195:(4′-Methyl-biphenyl-2-yl)-[5-(4-phenyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 26 and 4′-methyl-biphenyl-2-carboxylic acid. MS(ESI): mass calculated for C₃₀H₂₈N₄O, 460.58. m/z found 461.3 [M+H]⁺.

Example 196:[5-(4-Phenyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(4′-trifluoromethyl-biphenyl-2-yl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 26 and 4′-trifluoromethyl-biphenyl-2-carboxylicacid. MS (ESI): mass calculated for C₃₀H₅₃F₃N₄O, 514.56. m/z found 515.3[M+H]⁺.

Example 197:(4-Methoxy-2-methyl-phenyl)-(5-quinoxalin-2-yl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 4-methoxy-2-methyl-benzoic acid. MS (ESI):mass calculated for C₂₃H₂₄N₄O₂, 388.47. m/z found 389.2 [M+H]⁺.

Example 198:(3′-Chloro-biphenyl-2-yl)-[5-(4-phenyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 26 and 3′-chloro-biphenyl-2-carboxylic acid. MS(ESI): mass calculated for C₂₉H₂₅ClN₄O, 480.99. m/z found 481.2 [M+H]⁺.

Example 199:(2-Methoxy-phenyl)-[5-(4-methoxy-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 32 and 2-methoxybenzoic acid. MS (ESI): masscalculated for C₁₉H₂₂N₄O₃, 354.41. m/z found 355.2 [M+H]⁺.

Example 200:(2-Methoxy-phenyl)-[5-(4-methyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 27 and 2-methoxybenzoic acid. MS (ESI): masscalculated for C₁₉H₂₂N₄O₂, 338.41. m/z found 339.3 [M+H]⁺.

Example 201:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-methoxy-phenyl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2-methoxybenzoic acid. MS (ESI): masscalculated for C₂₀H₂₄N₄O₂, 352.44. m/z found 353.3 [M+H]⁺.

Example 202:2-[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carbonyl]-benzonitrile

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2-cyanobenzoic acid. MS (ESI): masscalculated for C₂₀H₂₁N₅O, 347.42. m/z found 348.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 8.51-8.39 (m, 2H), 7.37-7.32 (m, 1H), 7.25-7.06 (m, 3H),6.76 (t, J=13.7 Hz, 1H), 4.18-3.96 (m, 3H), 3.48-3.33 (m, 1H), 3.05 (dd,J=12.9, 6.4 Hz, 1H), 2.69-2.27 (m, 10H), 1.68-1.50 (m, 5H), 1.50-1.37(m, 3H).

Example 203:Cinnolin-4-yl-[5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and cinnoline-4-carboxylic acid. MS (ESI):mass calculated for C₂₁H₂₂N₆O, 374.45. m/z found 375.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 9.26 (s, 1H), 8.61 (dd, J=8.4, 1.1 Hz, 1H), 7.96-7.85(m, 2H), 7.83-7.74 (m, 1H), 6.33 (s, 1H), 4.13-4.07 (m, 1H), 3.92 (dd,J=11.7, 7.5 Hz, 1H), 3.84 (dd, J=13.0, 4.9 Hz, 1H), 3.78-3.68 (m, 2H),3.54-3.42 (m, 2H), 3.20-3.09 (m, 2H), 3.04-2.98 (m, 1H), 2.29 (s, 6H).

Example 204:(5-Fluoro-2-pyrimidin-2-yl-phenyl)-[5-(6-methyl-2-trifluoromethyl-pyrimidin-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 13 and Intermediate 31. MS (ESI): mass calculatedfor C₂₃H₂₀F₄N₆O, 472.45. m/z found 473.2 [M+H]⁺.

Example 205:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-[1,2,3]triazol-1-yl-phenyl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 3 and Intermediate 15 as starting materials. Inthis case Intermediate C was coupled to Intermediate 15 first then thet-butylcarboxylate was removed prior to the addition of2-chloro-4,6-methylpyrimidine. (ESI): mass calculated for C₂₁H₂₃N₇O,389.46. m/z found 390.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.99 (d, J=1.0Hz, 1H), 7.79 (d, J=0.9 Hz, 1H), 7.67-7.62 (m, 1H), 7.62-7.52 (m, 2H),7.49-7.45 (m, 1H), 7.27 (s, 1H), 3.87-3.65 (m, 3H), 3.54-3.44 (m, 2H),3.38-3.25 (m, 2H), 3.04-2.78 (m, 3H), 2.29 (s, 6H).

Example 206:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-[1,2,4]triazol-1-yl-phenyl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid.MS (ESI) mass calcd. for C₂₁H₂₃N₇O, 389.46. m/z found, 390.2 [M+H]⁺.

Example 207:[5-(4,6-Dimethoxy-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(3-phenyl-pyridin-2-yl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 39 and 3-phenyl-pyridine-2-carboxylic acid. MS(ESI): mass calculated for C₂₄H₂₅N₅O₃, 431.50. m/z found 432.3 [M+H]⁺.

Example 208:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(3-phenyl-pyridin-2-yl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 3-phenyl-pyridine-2-carboxylic acid. MS(ESI): mass calculated for C₂₄H₂₅N₅O, 399.5. m/z found 400.3 [M+H]⁺.

Example 209:[5-(6-Methyl-2-propyl-pyrimidin-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-[1,2,3]triazol-2-yl-phenyl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and 4-chloro-6-methyl-2-propyl-pyrimidine. MS(ESI): mass calculated for C₂₃H₂₇N₇O, 417.51. m/z found 418.2 [M+H]⁺.

Example 210:[5-(2-Methyl-pyrimidin-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-[1,2,3]triazol-2-yl-phenyl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and 4-chloro-2-methyl-pyrimidine. MS (ESI):mass calculated for C₂₀H₂₁N₇O, 375.43. m/z found 376.2 [M+H]⁺.

Example 211:[5-(6-Methyl-pyrazin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-[1,2,3]triazol-2-yl-phenyl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and 2-chloro-6-methyl-pyrazine. MS (ESI): masscalculated for C₂₀H₂₁N₇O, 375.43. m/z found 376.2 [M+H]⁺.

Example 212:[5-(3,6-Dimethyl-pyrazin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(5-fluoro-2-pyrimidin-2-yl-phenyl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 34 and Intermediate 13. MS (ESI): mass calculatedfor C₂₃H₂₃FN₆O, 418.47. m/z found 419.2 [M+H]⁺.

Example 213:[5-(3,6-Dimethyl-pyrazin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-[2-(2H-[1,2,4]triazol-3-yl)-phenyl]-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 34 and 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid.MS (ESI): mass calculated for C₂₁H₂₃N₇O, 389.46. m/z found 390.2 [M+H]⁺.

Example 214:[5-(2-Pyrrolidin-1-yl-6-trifluoromethyl-pyrimidin-4-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-[1,2,3]triazol-2-yl-phenyl)-methanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 20 and4-chloro-2-pyrrolidin-1-yl-6-trifluoromethyl-pyrimidine acid. MS (ESI):mass calculated for C₂₄H₂₅F₃N₅O, 498.51. m/z found 499.2 [M+H]⁺.

Example 215:2-(2,6-Dimethylpyrimidin-4-yl)-5-{[5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Intermediate23, substituting(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone(Intermediate 21) for hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acidtert-butyl ester and 4-chloro-2,6-dimethylpyrimidine for2-chloro-4,6-dimethyl-pyrimidine in Step A. MS (ESI) mass calcd forC₂₁H₂₂FN₇O, 407.19. m/z found, 408.2 [M+H]⁺.

Prophetic Examples 216-218 may be synthesized using the general schemesprovided above.

Example 216:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-nitro-6-[1,2,3]triazol-2-yl-phenyl)-methanone

MS (ESI) mass calcd. for C₂₁H₂₂N₈O₃, 434.45.

Example 217:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-furan-2-yl-phenyl)-methanone

MS (ESI) mass calcd. for C₂₃H₂₄N₄O₃, 388.46.

Example 218:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-methyl-5-phenyl-thiazol-4-yl)-methanone

MS (ESI) mass calcd. for C₂₃H₂₅N₅OS, 419.54.

Example 219:2-[(2,3-Dimethylphenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2,3-dimethylbenzoic acid. MS (ESI): masscalculated for C₂₁H₂₆N₄O, 350.47. m/z found 351.3 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 7.16-7.05 (m, 2H), 7.02 (d, J=7.1 Hz, 1H), 6.30 (s, 1H),4.00-3.86 (m, 2H), 3.78 (dd, J=11.6, 7.4 Hz, 1H), 3.70-3.58 (m, 2H),3.49-3.38 (m, 2H), 3.17-3.02 (m, 2H), 2.99-2.92 (m, 1H), 2.35-2.28 (s,6H), 2.27 (s, 3H), 2.19 (s, 3H).

Example 220:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(3-fluoro-2-methylphenyl)carbonyl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 3-fluoro-2-methylbenzoic acid. MS (ESI):mass calculated for C₂₀H₂₃FN₄O, 354.4. m/z found 355.3 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.22-7.14 (m, 1H), 7.06-6.95 (m, 2H), 6.30 (s, 1H),4.00-3.86 (m, 2H), 3.78 (dd, J=11.6, 7.3 Hz, 1H), 3.70-3.58 (m, 2H),3.52-3.39 (m, 2H), 3.19-3.02 (m, 2H), 3.02-2.92 (m, 1H), 2.30 (s, 6H),2.21 (d, J=2.0 Hz, 3H).

Example 221:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[5-fluoro-2-(trifluoromethyl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 5-fluoro-2-(trifluoromethyl)benzoic acid.MS (ESI): mass calculated for C₂₀H₂₀F₄N₄O, 408.4. m/z found 409.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.71 (dd, J=8.8, 5.0 Hz, 1H), 7.22-7.14(m, 1H), 7.06 (dd, J=8.1, 2.3 Hz, 1H), 6.31 (s, 1H), 4.01-3.87 (m, 2H),3.79 (dd, J=11.7, 7.3 Hz, 1H), 3.69-3.56 (m, 2H), 3.53-3.41 (m, 2H),3.19-3.04 (m, 2H), 3.05-2.97 (m, 1H), 2.30 (s, 6H).

Example 222:2-[(4-Chloro-2-methoxyphenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 4-chloro-2-methoxybenzoic acid. MS (ESI):mass calculated for C₂₀H₂₃ClN₄O₂, 386.9. m/z found 389.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.18 (d, J=8.0 Hz, 1H), 6.97 (dd, J=8.0, 1.8 Hz, 1H),6.89 (d, J=1.7 Hz, 1H), 6.29 (s, 1H), 3.98-3.82 (m, 2H), 3.80 (s, 3H),3.78-3.73 (m, 1H), 3.68-3.59 (m, 2H), 3.55-3.44 (m, 2H), 3.19 (dd,J=11.1, 5.0 Hz, 1H), 3.13-2.90 (m, 2H), 2.29 (s, 6H).

Example 223:2-[(5-Chloro-2-methylphenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 5-chloro-2-methylbenzoic acid. MS (ESI):mass calculated for C₂₀H₂₃ClN₄O, 370.9. m/z found 371.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.26-7.21 (m, 1H), 7.18-7.13 (m, 2H), 6.31 (s, 1H),4.00-3.86 (m, 2H), 3.79 (dd, J=11.6, 7.3 Hz, 1H), 3.68-3.57 (m, 2H),3.51-3.42 (m, 2H), 3.17-2.94 (m, 3H), 2.30 (s, 6H), 2.26 (s, 3H).

Example 224:2-[(2,5-Dimethylphenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2,5-dimethylbenzoic acid. MS (ESI): masscalculated for C₂₁H₂₆N₄O, 350.5. m/z found 351.3 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 7.11-7.03 (m, 2H), 6.99 (s, 1H), 6.30 (s, 1H), 4.00-3.87(m, 2H), 3.78 (dd, J=11.5, 7.4 Hz, 1H), 3.70-3.58 (m, 2H), 3.50-3.42 (m,2H), 3.15-2.90 (m, 3H), 2.32 (s, 3H), 2.32 (s, 3H), 2.24 (s, 3H).

Example 225:2-[(2,6-Dimethylphenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2,6-dimethylbenzoic acid. MS (ESI): masscalculated for C₂₁H₂₆N₄O, 350.5. m/z found 351.3 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 7.13 (t, J=7.6 Hz, 1H), 7.51-7.00 (m, 2H), 6.30 (s, 1H),4.15-3.87 (m, 2H), 3.85-3.75 (m, 1H), 3.73-3.67 (m, 1H), 3.63-3.55 (m,1H), 3.50-3.44 (m, 1H), 3.40-3.33 (m, 1H), 3.08-2.90 (m, 3H), 2.28 (s,6H), 2.21 (s, 3H), 1.80 (s, 3H).

Example 226:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(5-fluoro-2-methylphenyl)carbonyl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 5-fluoro-2-methylbenzoic acid. MS (ESI):mass calculated for C₂₀H₂₃FN₄O, 354.4. m/z found 355.3 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.16 (dd, J=8.5, 5.4 Hz, 1H), 6.98-6.92 (m, 1H), 6.90(dd, J=8.5, 2.7 Hz, 1H), 6.30 (s, 1H), 3.98-3.87 (m 2H), 3.79 (dd,J=11.6, 7.3 Hz, 1H), 3.68-3.57 (m, 2H), 3.50-3.43 (m, 2H), 3.16-2.94 (m,3H), 2.30 (s, 6H), 2.26 (d, J=8.6 Hz, 3H).

Example 227:2-[(2,4-Dimethylphenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2,4-dimethylbenzoic acid. MS (ESI): masscalculated for C₂₁H₂₆N₄O, 350.5. m/z found 351.3 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 7.02 (s, 2H), 6.29 (s, 0H), 3.92 (ddd, J=19.2, 12.2, 7.7Hz, 2H), 3.77 (dd, J=11.6, 7.4 Hz, 0H), 3.63 (ddd, J=18.1, 12.2, 4.9 Hz,1H), 3.52-3.39 (m, 1H), 3.06 (ddd, J=50.9, 27.4, 6.2 Hz, 0H), 2.30 (d,J=6.6 Hz, 3H), 2.28-2.24 (m, 3H).

Example 228:2-[(2,5-Diethoxyphenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2,5-diethoxybenzoic acid. MS (ESI): masscalculated for C₂₃H₃₀N₄O₃, 410.5. m/z found 411.3 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 6.89-6.77 (m, 3H), 6.28 (s, 1H), 4.04-3.83 (m, 6H),3.80-3.74 (m, 1H), 3.70-3.44 (m, 4H), 3.27 (s, 1H), 3.13-2.90 (m, 2H),2.26 (s, 6H), 1.44-1.23 (m, 6H).

Example 229:2-[(2,6-Diethoxyphenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2,6-diethoxybenzoic acid. MS (ESI): masscalculated for C₂₃H₃₀N₄O₃, 410.5. m/z found 411.3 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 7.19 (t, J=8.4 Hz, 1H), 6.55-6.46 (m, 2H), 6.27 (s, 1H),4.06 (q, J=7.0 Hz, 2H), 3.98 (q, J=7.0 Hz, 2H), 3.94-3.82 (m, 2H),3.79-3.65 (m, 2H), 3.61 (dd, J=11.6, 5.0 Hz, 1H), 3.57-3.42 (m, 2H),3.17 (dd, J=11.0, 5.0 Hz, 1H), 3.11-2.87 (m, 2H), 2.31-2.27 (m, 6H),1.44-1.25 (m, 6H).

Example 230:2-[(2-Chloro-6-methylphenyl)carbonyl]-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2-chloro-6-methylbenzoic acid. MS (ESI):mass calculated for C₂₀H₂₃ClN₄O, 370.9. m/z found 371.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): (rotamers observed) 7.24-7.14 (m, 2H), 7.15-7.07 (m,1H), 6.31-6.28 (m, 1H), 4.06-3.85 (m, 2H), 3.85-3.75 (m, 1H), 3.74-3.36(m, 1H), 3.65-3.52 (m, 2H), 3.45-3.51 (m, 1H), 3.37-3.30 (m, 1H),3.25-3.14 (m, 1H), 3.14-2.94 (m, 2H), 2.37-2.23 (m, 9H).

Example 231:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-fluoro-2-(pyrimidin-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 15,substituting Intermediate 87 for 3-fluoro-2-[1,2,3]triazol-2-yl-benzoicacid. MS (ESI) mass calcd. for C₂₃H₂₃FN₆O, 418.47. m/z found, 419.2[M+H]⁺.

Example 232:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-iodophenyl)methanone

The title compound was prepared in a manner analogous to Example 15substituting 2-iodo-3-fluorobenzoic acid for3-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid. MS (ESI) mass calcd. forC₁₉H₂₀FIN₄O, 466.3. m/z found, 467.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.36 (ddd, J=8.2, 7.5, 5.2 Hz, 1H), 7.04 (ddd, J=8.5, 7.7, 1.3 Hz, 2H),6.30 (s, 1H), 3.94 (ddd, J=20.9, 12.2, 7.6 Hz, 2H), 3.79 (dd, J=11.7,7.2 Hz, 1H), 3.69 (dd, J=12.8, 4.6 Hz, 1H), 3.64 (dd, J=11.7, 5.1 Hz,1H), 3.58-3.51 (m, 1H), 3.47 (dd, J=10.8, 7.4 Hz, 1H), 3.16-2.98 (m,3H), 2.29 (s, 6H).

Example 233:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-(trifluoromethyl)pyridin-3-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 23 and 2-(trifluoromethyl)nicotinic acid. MS(ESI): mass calculated for C₁₉H₂₀F₃N₅O, 391.4. m/z found 392.9 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.77 (dd, J=4.7, 1.0 Hz, 1H), 7.74 (d, J=6.9Hz, 1H), 7.55 (dd, J=12.4, 6.2 Hz, 1H), 6.31 (s, 1H), 3.99 (dd, J=12.8,7.7 Hz, 1H), 3.90 (dd, J=11.7, 7.6 Hz, 1H), 3.80 (dd, J=11.6, 7.3 Hz,1H), 3.71-3.57 (m, 2H), 3.50-3.41 (m, 2H), 3.16-3.06 (m, 2H), 3.06-2.97(m, 1H), 2.34 (s, 5H).

Example 234:2-Bromopyridin-3-yl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner analogous to Example 1utilizing Intermediate 23 and 2-bromopyridine-3-carboxylic acid. MS(ESI): mass calculated for C₁₈H₂₀BrN₅O, 401.09. m/z found 402.9 [M+H]⁺.¹H NMR (600 MHz, CDCl₃): 8.41 (dd, J=4.7, 1.8, 1H), 7.66-7.54 (m, 1H),7.34 (dd, J=7.4, 4.8, 1H), 6.38-6.24 (m, 1H), 3.94 (dd, J=12.1, 7.6,2H), 3.80 (dd, J=11.5, 7.3, 1H), 3.74-3.46 (m, 4H), 3.31-3.01 (m, 3H),2.40-2.23 (m, 6H).

Example 235:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(pyrimidin-2-yl)pyridin-3-yl)methanone

To a solution of2-bromopyridin-3-yl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone(Example 234) (50 mg, 0.14 mmol), 2-tributylstannylpyrimidine (50 mg,0.14 mmol), and copper iodide (2.6 mg, 0.014 mmol) in 1,4 dioxane (1 mL)was added Pd(PPh₃)₄ (16 mg, 0.014 mmol). The reaction was irradiated ina microwave reactor at 160° C. for one hour. The resulting solution wasfiltered through Celite®, washed with DCM, and concentrated.Purification (FCC) (MeOH (NH₃)/DCM) gave the title compound (35 mg,64%). MS (ESI): mass calculated for C₂₂H₂₃N₇O, 401.20. m/z found 402.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.85 (s, 3H), 7.70 (d, J=6.7, 1H),7.48-7.42 (m, 1H), 7.21 (d, J=4.4, 1H), 6.32-6.24 (m, 1H), 3.93-3.79 (m,2H), 3.75-3.61 (m, 3H), 3.52 (s, 1H), 3.52-3.42 (m, 1H), 3.17 (dd,J=10.8, 5.0, 1H), 3.09-2.88 (m, 2H), 2.37-2.22 (m, 6H).

Example 236:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)methanone

To a solution of2-bromopyridin-3-yl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone(Example 234) (50 mg, 0.12 mmol), 4-(tetrahydropyran-2H-yl)-1Hpyrazole-5 boronic acid pinacol ester (35 mg, 0.12 mmol), TBAB (4.0 mg,0.012 mmol), and PdCl₂(dppf) (10 mg, 0.012 mmol) in toluene (0.6 mL) wasadded 2N aq. Na₂CO₃ (0.12 ml, 0.25 mmol). The reaction was irradiated ina microwave reactor at 110° C. for one hour. The resulting solution wasfiltered through Celite®, washed with DCM, and concentrated.Purification (FCC) (MeOH (NH₃)/DCM) gave the title compound (52 mg,88%). MS (ESI): mass calculated for C₂₆H₃₁N₇O₂, 473.25. m/z found 474.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.72 (dd, J=4.7, 1.8, 1H), 7.76 (dd,J=8.0, 1.7, 1H), 7.62-7.45 (m, 1H), 7.34 (ddd, J=7.7, 4.8, 1.5, 1H),6.56 (dd, J=18.2, 9.1, 1H), 6.33-6.23 (m, 1H), 3.91-3.71 (m, 2H),3.72-3.53 (m, 3H), 3.53-3.36 (m, 2H), 3.36-3.06 (m, 3H), 2.98-2.70 (m,3H), 2.65 (d, J=6.4, 1H), 2.51 (d, J=10.0, 1H), 2.28 (d, J=9.8, 6H),2.18-2.01 (m, 2H), 1.94 (s, 3H).

Example 237:(2-(1H-Pyrazol-5-yl)pyridin-3-yl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

To a solution of(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)methanone(Example 236) (210 mg, 0.43 mmol) in THE (10 mL) and H₂O (1 mL) wasadded 4 N aq. HCl (1 mL). The reaction was let stir for 2 hours,neutralized with 3 N aq. NaOH, and extracted with DCM (3×20 mL). Theorganics were combined, dried with Na₂SO₄, and concentrated.Purification (FCC) (MeOH (NH₃)/DCM) gave the title compound (128 mg,73%) (MS (ESI): mass calculated for C₂₁H₂₃N₇O, 389.20. m/z found 390.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.68-8.59 (m, 1H), 7.63 (d, J=9.1, 2H),7.32-7.20 (m, 1H), 6.80 (d, J=2.2, 1H), 6.33-6.19 (m, 1H), 3.92-3.55 (m,5H), 3.54-2.78 (m, 5H), 2.37-2.24 (m, 6H).

Example 238:(2-(2H-1,2,3-Triazol-2-yl)pyridin-3-yl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

To a solution of2-bromopyridin-3-yl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone(Example 234) (150 mg, 0.37 mmol), 1H-1,2,3 triazole (43 μL, 0.75 mmol),CSCO₃ (247 mg, 0.75 mmol), in H₂O (2 μL) and 1,4 dioxane (2 mL) wasadded (R,R)—(−)—N,N′-dimethyl-1,2-cyclohexyldiamine (12 μL, 0.75 mmol)and CuI (3.5 mg, 0.86 mmol). The reaction mixture was irradiated in amicrowave reactor at 160° C. for 2 h. The resulting solution wasfiltered through Celite®, washed with DCM, and concentrated.Purification (FCC) (MeOH (NH₃)/DCM) gave the title compound (8 mg, 6%).MS (ESI): mass calculated for C₂₀H₂₂N₅O, 390.19; m/z found 391.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.65 (dd, J=4.8, 1.8, 1H), 7.83 (dt, J=13.3,6.6, 2H), 7.43 (dt, J=7.6, 4.5, 1H), 6.38-6.23 (m, 2H), 4.02-3.28 (m,6H), 3.10-3.06 (m, 4H), 2.42-2.22 (m, 6H).

Example 239:(3-Fluoro-2-(pyrimidin-2-yl)phenyl)(5-(4,5,6-trimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 42 and 3-fluoro-2-(pyrimidin-2-yl)benzoic acid.MS (ESI): mass calculated for C₂₄H₂₅FN₆O, 432.21. m/z found 433.3[M+H]⁺. ¹H NMR (600 MHz, CDCl₃): 8.41 (dd, J=4.7, 1.8, 2H), 7.66-7.54(m, 2H), 7.34 (dd, J=7.4, 4.8, 2H), 3.94 (dd, J=12.1, 7.6, 2H), 3.80(dd, J=11.5, 7.3, 1H), 3.74-3.46 (m, 4H), 3.31-3.01 (m, 3H), 2.40-2.13(m, 9H).

Example 240:(3-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4,5,6-trimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 42 and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoicacid. MS (ESI): mass calculated for C₂₂H₂₄FN₇O, 421.20. m/z found 422.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.82-7.77 (m, 2H), 7.51-7.44 (m, 1H),7.31 (ddd, J=9.8, 8.4, 1.3, 1H), 7.25-7.20 (m, 1H), 3.86-3.60 (m, 3H),3.59-3.42 (m, 4H), 3.14 (dd, J=10.9, 5.3, 1H), 2.94 (dd, J=10.9, 7.1,2H), 2.38-2.27 (m, 6H), 2.07 (d, J=7.2, 3H).

Example 241:(5-Methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4,5,6-trimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 42 and 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoicacid. MS (ESI): mass calculated for C₂₃H₂₇N₇O₂, 433.22. m/z found 434.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.84 (d, J=9.0, 1H), 7.69 (s, 2H), 7.01(dd, J=9.0, 2.8, 1H), 6.91 (d, J=2.8, 1H), 3.91-3.74 (m, 5H), 3.70-3.58(m, 2H), 3.55 (dd, J=11.4, 5.2, 1H), 3.47-3.28 (m, 2H), 3.04-2.82 (m,3H), 2.41-2.25 (m, 5H), 2.13-2.01 (m, 4H).

Example 242:(3-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(6-fluoroquinazolin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 43 and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoicacid. MS (ESI): mass calculated for C₂₃H₁₉F₂N₇O, 447.16. m/z found 448.1[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.99 (s, 1H), 7.77 (d, J=15.8, 2H),7.61 (dd, J=11.0, 5.5, 1H), 7.53-7.43 (m, 2H), 7.37-7.29 (m, 2H), 7.24(s, 1H), 3.93 (d, J=9.9, 1H), 3.79 (dd, J=12.3, 7.4, 2H), 3.71-3.62 (m,1H), 3.62 (s, 3H), 3.20 (dd, J=11.0, 5.3, 1H), 3.12-2.98 (m, 2H).

Example 243:(3-Fluoro-2-(pyrimidin-2-yl)phenyl)(5-(6-fluoroquinazolin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 43 and 3-fluoro-2-(pyrimidin-2-yl)benzoic acid.MS (ESI): mass calculated for C₂₅H₂₀F₂N₆O, 458.17. m/z found 459.1[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.98 (d, J=8.1, 1H), 8.82-8.74 (m, 2H),7.61 (dt, J=12.7, 6.4, 1H), 7.53-7.41 (m, 2H), 7.31 (td, J=8.0, 2.7,1H), 7.25-7.18 (m, 2H), 7.15 (t, J=4.9, 1H), 4.00-3.88 (m, 1H),3.89-3.69 (m, 3H), 3.68-3.52 (m, 3H), 3.36 (dd, J=10.9, 4.6, 1H),3.14-2.97 (m, 2H).

Example 244:(5-(6,7-Difluoroquinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 44 and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoicacid. MS (ESI): mass calculated for C₂₃H₁₈F₃N₇O, 465.15. m/z found 466.1[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.28 (s, 1H), 7.75 (d, J=20.8, 2H),7.65 (dd, J=10.6, 8.4, 1H), 7.50 (tt, J=9.6, 4.8, 1H), 7.43 (dd, J=11.4,8.0, 1H), 7.39-7.31 (m, 1H), 7.25 (dd, J=12.5, 4.9, 1H), 4.00-3.86 (m,1H), 3.81 (dd, J=10.0, 5.6, 2H), 3.66-3.49 (m, 4H), 3.32-3.16 (m, 3H).

Example 245:(5-(6,7-Difluoroquinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 44 and 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoicacid. MS (ESI): mass calculated for C₂₄H₂₁F₂N₇O₂, 477.2. m/z found 478.1[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.25 (s, 1H), 7.84 (t, J=7.6, 1H), 7.64(dt, J=19.7, 10.8, 3H), 7.42 (dd, J=11.4, 8.0, 1H), 7.03 (dd, J=9.0,2.8, 1H), 6.92 (d, J=2.8, 1H), 3.97-3.84 (m, 5H), 3.64 (dd, J=18.2,14.6, 5H), 3.12 (dd, J=19.8, 8.6, 3H).

Example 246:(5-(6,7-Difluoroquinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 44 and 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoicacid. MS (ESI): mass calculated for C₂₃H₁₈F₃N₇O, 465.2. m/z found 466.1[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.32-8.24 (m, 1H), 7.90-7.79 (m, 2H),7.68 (s, 1H), 7.65 (ddd, J=10.7, 8.5, 4.2, 1H), 7.55-7.38 (m, 2H),7.22-7.10 (m, 1H), 4.13-3.48 (m, 7H), 3.40-3.05 (m, 3H).

Example 247:(2-Bromo-3-fluorophenyl)(5-(6-fluoroquinazolin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 43 and 2-bromo-3-fluorobenzoic acid. MS (ESI):mass calculated for C₂₁H₁₇BrF₂N₄O, 458.1. m/z found 459.0 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 8.95 (d, J=19.8, 1H), 8.01 (s, 1H), 7.59 (dt, J=13.3,6.7, 1H), 7.52-7.40 (m, 1H), 7.40-7.28 (m, 1H), 7.18-7.05 (m, 2H), 4.01(dt, J=12.8, 8.4, 2H), 3.95-3.85 (m, 1H), 3.80-3.48 (m, 4H), 3.27-3.04(m, 3H).

Example 248:(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-fluoro-2-(5-methylpyridin-2-yl)phenyl)methanone

(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-fluoro-2-(5-methylpyridin-2-yl)phenyl)methanone.The title compound was prepared in a manner analogous to Intermediate50, Step A, substituting(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-fluoro-2-iodophenyl)methanonefor 2-iodo-3-fluorobenzonitrile, 5-methyl-2-(tributylstannyl)pyridinefor 2-tributylstannane pyrimidine, dioxane for DME and heating to 130°C. for 60 minutes. The reactions were filtered through celite, rinsedwith EtOAc and then concentrated and purified on RP agilent HPLC andfractions lyophilized. MS (ESI) mass calcd. for C₂₅H₂₆FN₅O, 431.21;found 432.2 [M+H]⁺.

Example 249:(2-Bromopyridin-3-yl)(5-(4,5,6-trimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner analogous to Example 1utilizing Intermediate 42 and 2-bromopyridine-3-carboxylic acid. MS(ESI): mass calculated for C₁₈H₂₂BrN₅O, 415.10. m/z found 416.1 [M+H]⁺.¹H NMR (600 MHz, CDCl₃): 8.44 (dd, J=4.7, 1.6, 1H), 7.33 (dd, J=7.6,4.7, 1H), 6.38-6.24 (m, 1H), 3.94-3.90 (m, 2H), 3.88-3.84 (m, 1H),3.74-3.50 (m, 4H), 3.31-3.01 (m, 3H), 2.40-2.23 (m, 6H), 2.12-2.06 (m,3H).

Example 250:(2-(1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)(5-(4,5,6-trimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner similar to Example 236,utilizing Example 249 and 4-(terahydropyran-2H-yl)-1H pyrazole-5 boronicacid pinacol ester. MS (ESI): mass calculated for C₂₇H₃₃N₇O₂, 487.27.m/z found 488.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 8.78-8.72 (m, 1H),7.80-7.75 (m, 1H), 7.62-7.45 (m, 1H), 7.34 (dd, J=4.8, 1.5, 1H),6.33-6.23 (m, 1H), 3.91-3.78 (m, 2H), 3.72-3.53 (m, 3H), 3.53-3.36 (m,2H), 3.36-3.15 (m, 3H), 2.98-2.70 (m, 3H), 2.65 (d, J=6.8, 1H),2.38-2.27 (m, 6H), 2.10-2.06 (m, 3H), 2.18-2.01 (m, 2H), 1.94 (s, 3H).

Example 251:(2-(1H-Pyrazol-5-yl)pyridin-3-yl)(5-(4,5,6-trimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner similar to Example 237,utilizing(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)(5-(4,5,6-trimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone(Example 250). MS (ESI): mass calculated for C₂₃H₁₈F₃N₇O, 403.21. m/zfound 404.2 [M+H]⁺. 1H NMR (500 MHz, CDCl₃): 11.90 (s, 1H), 8.65 (dd,J=4.7, 1.5, 1H), 7.65 (dd, J=7.7, 1.6, 1H), 7.50 (d, J=7.0, 1H),7.34-7.21 (m, 1H), 6.81 (s, 1H), 3.66-3.60 (m, 6H), 3.26 (s, 4H),2.39-2.25 (m, 6H), 2.09 (d, J=40.1, 3H).

Example 252:6-[5-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2-methylpyrimidin-4(3H)-one

To a solution of Intermediate 16 (35.3 mg, 0.117 mmol) in n-butanol (0.5mL) was added triethylamine (0.065 mL, 0.47 mmol) and6-chloro-2-methylpyrimidin-4-ol (33.9 mg, 0.234 mmol). The mixture washeated to 150° C. in the microwave for 18 minutes. The reaction wasconcentrated and purified by reverse phase HPLC to give the titlecompound (21.4 mg, 45%). MS (ESI): mass calculated for C₂₀H₂₀FN₇O₂,409.4. m/z found [M+H]⁺410.2. ¹H NMR (400 MHz, CDCl₃): 7.91-7.76 (m,3H), 7.54-7.42 (m, 1H), 7.15 (t, J=8.5 Hz, 1H), 4.07-2.94 (m, 11H), 2.37(d, J=8.8 Hz, 3H).

Example 253:2-(2,6-Dimethylpyrimidin-4-yl)-5-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

To a solution of Intermediate 48 (15.8 mg, 0.048 mmol) was added DMF(0.4 mL), 4-chloro-2,6-dimethylpyrimidine (8.2 mg, 0.057 mmol) andcesium carbonate (38.8 mg, 0.119 mmol). The mixture was heated to 100°C. for 18 hours, diluted with water and extracted with ethyl acetate.The organic layer was dried over Na₂SO₄ and concentrated. The residuewas purified by reverse phase HPLC to give the title compound (12.9 mg,62%). MS (ESI): mass calculated for C₂₃H₂₄FN₅OS, 437.5; m/z found[M+H]⁺438.2. ¹H NMR (400 MHz, CDCl₃): 7.51-7.41 (m, 2H), 7.06-6.95 (m,2H), 6.29 (s, 1H), 3.892-3.76 (m, 2H), 3.73-3.51 (m, 3H), 3.44 (dd,J=11.6, 5.0 Hz, 1H), 3.32 (dd, J=11.6, 4.5 Hz, 1H), 3.10 (dd, J=11.3,5.3 Hz, 1H), 3.02-2.80 (m, 2H), 2.70 (s, 3H), 2.31 (d, J=20.0 Hz, 6H).

Example 254:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[5-(4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 253substituting 2-chloro-4,6-dimethylpyrimidine for4-chloro-2,6-dimethylpyrimidine. MS (ESI): mass calculated forC₂₃H₂₄FN₅OS, 437.5. m/z found [M+H]⁺438.2. ¹H NMR (400 MHz, CDCl₃):7.53-7.41 (m, 2H), 7.06-6.97 (m, 2H), 6.29 (s, 1H), 3.90-3.76 (m, 2H),3.69-3.49 (m, 3H), 3.44 (dd, J=11.6, 5.0 Hz, 1H), 3.32 (dd, J=11.6, 4.5Hz, 1H), 3.10 (dd, J=11.3, 5.3 Hz, 1H), 3.02-2.82 (m, 2H), 2.70 (s, 3H),2.29 (s, 6H).

Example 255:6-[5-{[5-(4-Fluorophenyl)-2-methyl-1,3-thiazol-4-yl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-2-methylpyrimidin-4(3H)-one

The title compound was prepared in a manner analogous to Example 252substituting Intermediate 48 for Intermediate 16. MS (ESI): masscalculated for C₂₂H₂₂FN₅O₂S, 439.5. m/z found 440.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 12.77 (s, 1H), 7.50-7.43 (m, 2H), 7.09-7.02 (m, 2H),3.90-3.82 (m, 2H), 3.66-3.49 (m, 4H), 3.29-2.82 (m, 5H), 2.71 (s, 3H),2.36 (s, 3H).

Example 256:6-{5-[(5-Fluoro-2-pyrimidin-2-ylphenyl)carbonyl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl}-2-methylpyrimidin-4(3H)-one

The title compound was prepared in a manner analogous to Example 252,substituting(5-fluoro-2-(pyrimidin-2-yl)phenyl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanonefor Intermediate 16. MS (ESI): mass calculated for C₂₂H₂₁FN₆O₂, 420.5;m/z found 421.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 12.85 (s, 1H), 8.73 (d,J=4.9 Hz, 2H), 8.35 (dd, J=8.8, 5.6 Hz, 1H), 7.24-7.13 (m, 2H), 7.07(dd, J=8.4, 2.6 Hz, 1H), 3.90 (dd, J=12.6, 7.7 Hz, 1H), 3.76-3.65 (m,3H), 3.55-3.48 (m, 2H), 3.24-2.90 (m, 4H), 2.36 (d, J=8.7 Hz, 3H).

Example 257:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 23 and Intermediate 4. MS (ESI): mass calculatedfor C₂₃H₂₄FN₅O, 407.19. m/z found 408.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.80-7.68 (m, 3H), 7.39 (dd, J=8.4, 5.8, 1H), 7.17-7.09 (m, 1H), 6.40(s, 1H), 6.17 (s, 2H), 3.89 (dd, J=12.7, 7.6, 2H), 3.69 (dd, J=12.8,4.3, 2H), 3.61-3.48 (m, 2H), 3.45-3.32 (m, 2H), 3.25 (dd, J=9.5, 5.0,2H), 1.25 (s, 6H).

Example 258:(5-(4,6-Dimethoxypyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 45 and Intermediate 12. MS (ESI): mass calculatedfor C₂₁H₂₂FN₇O₃, 439.18. m/z found 440.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 7.89-7.80 (m, 2H), 7.73 (s, 1H), 7.53-7.43 (m, 1H), 7.15 (tdd,J=8.4, 3.7, 0.9, 1H), 5.39 (d, J=2.4, 1H), 4.02-3.48 (m, 13H), 3.31-2.89(m, 3H).

Example 259:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-methyl-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 23 and Intermediate 11. MS (ESI): mass calculatedfor C₂₂H₂₅N₇O, 403.21. m/z found 404.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.84-7.75 (m, 2H), 7.69 (s, 1H), 7.38 (td, J=7.9, 2.4, 1H), 7.25-7.22(m, 1H), 6.29 (d, J=3.8, 1H), 3.98-3.30 (m, 8H), 3.01 (dd, J=11.5, 6.6,2H), 2.30 (d, J=3.6, 3H), 1.57 (s, 6H).

Example 260:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 23 and 3-methyl-2-(2H-1,2,3-triazol-2-yl)benzoicacid (Intermediate 82). MS (ESI): mass calculated for C₂₂H₂₅N₇O, 403.21.m/z found 404.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.76 (s, 1H), 7.44-7.34(m, 2H), 7.25 (s, 1H), 7.24 (d, J=1.9, 1H), 6.30 (s, 1H), 3.88-3.40 (m,8H), 3.23 (dd, J=11.0, 4.9, 1H), 3.00-2.83 (m, 1H), 2.36-2.26 (m, 3H),2.24 (d, J=16.1, 3H), 1.63 (s, 3H).

Example 261:(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-nitropyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 46 and Intermediate 12. MS (ESI): mass calculatedfor C₁₉H₁₇FN₈O₃, 424.14. m/z found 425.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 9.10 (ddd, J=9.9, 5.7, 3.3, 2H), 7.90-7.79 (m, 2H), 7.74 (d,J=6.6, 1H), 7.55-7.44 (m, 1H), 7.22-7.10 (m, 1H), 4.13-3.60 (m, 7H),3.40-3.07 (m, 3H).

Example 262: Methyl2-(5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate

A mixture of Intermediate 16 (30 mg, 0.9 mmol), methyl2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (22 mg, 0.09 mmol),Cs₂CO₃ (92.4 mg, 0.28 mmol), in DMA (1 mL) was heated to 100° C. for 72hours. The mixture was cooled to rt diluted with H₂O and extracted withEtOAc. The organics were combined, dried and concentrated under reducedpressure. Purification (FCC) (10% MeOH, 0.1% NH₄OH in DCM/DCM) affordedthe title compound (19 mg, 37%) MS (ESI): mass calculated forC₂₂H₁₉F₄N₇O₃, 505.15. m/z found 506.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):8.98-8.85 (m, 1H), 7.92-7.78 (m, 2H), 7.73 (d, J=2.8, 1H), 7.54-7.42 (m,1H), 7.15 (td, J=8.4, 4.9, 1H), 4.15-3.45 (m, 11H), 3.41-2.95 (m, 3H).The aqueous layer was acidified with 1 N HCl and extracted with EtOAc.The organics were combined, dried and concentrated under reducedpressure. Purification (FCC) (0-100% soln of 5% MeOH, 0.5% HOAc inDCM/DCM) to afford2-(5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylicacid (22 mg, 44%).

Example 263:2-(5-(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylicAcid

The title compound was isolated from the synthesis of Example 262. MS(ESI): mass calculated for C₂₁H₁₇F₄N₇O₃, 491.13. m/z found 492.1 [M+H]⁺.¹H NMR (400 MHz, CD₃OD): 8.90 (t, J=11.7, 1H), 7.97 (s, 1H), 7.94-7.79(m, 2H), 7.69-7.58 (m, 1H), 7.29 (dt, J=25.1, 12.6, 1H), 4.05-3.50 (m,7H), 3.18 (tdd, J=19.6, 13.8, 6.8, 3H).

Example 264:(2-(4H-1,2,4-Triazol-4-yl)phenyl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 23 and 2-(4H-1,2,4-triazol-4-yl)benzoic acid. MS(ESI): mass calculated for C₂₂H₁₉F₄N₇O₃, 505.15. m/z found 506.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 8.49 (s, 2H), 7.54 (dd, J=7.6, 1.9, 3H),7.45-7.37 (m, 1H), 6.31 (d, J=11.3, 1H), 3.88-3.65 (m, 4H), 3.50 (dd,J=12.0, 4.4, 2H), 3.33 (dt, J=11.2, 5.6, 1H), 3.08-2.80 (m, 3H),2.28-2.26 (m, 6H).

Example 265:2-(5-(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-6-methylpyrimidine-4-carboxylicAcid

The title compound was prepared in a manner analogous to Example 262,substituting methyl 2-chloro-6-methylpyrimidine-4-carboxylate for methyl2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate. MS (ESI): masscalculated for C₂₁H₂₀FN₇O₃, 437.16. m/z found 438.2 [M+H]⁺. ¹H NMR (400MHz, CD₃OD): 7.96 (d, J=6.2, 1H), 7.92-7.79 (m, 2H), 7.67-7.57 (m, 1H),7.29 (d, J=8.4, 1H), 7.09 (s, 1H), 4.01-3.53 (m, 7H), 3.28-2.99 (m, 3H),2.40-2.36 (m, 3H).

Example 266:(4,5-Difluoro-2-(4H-1,2,4-triazol-4-yl)phenyl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 23 and4,5-difluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI): masscalculated for C₂₁H₂₁F₂N₇O, 425.18. m/z found 425.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 7.86 (dd, J=10.8, 7.0, 1H), 7.74 (s, 2H), 7.26-7.19 (m,1H), 6.30 (s, 1H), 3.86 (dd, J=11.8, 7.6, 2H), 3.66-3.50 (m, 5H),3.10-2.86 (m, 3H), 2.36-2.23 (m, 6H).

Example 267:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-methyl-2-(1H-1,2,3-triazol-1-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 23 and 3-methyl-2-(1H-1,2,3-triazol-1-yl)benzoicacid. MS (ESI): mass calculated for C₂₂H₂₅N₇O, 403.21. m/z found 404.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.87-7.77 (m, 1H), 7.52-7.38 (m, 2H),7.25 (d, J=4.7, 2H), 6.28 (s, 1H), 3.76 (dd, J=11.6, 7.2, 2H), 3.65-3.29(m, 6H), 3.12 (dd, J=11.1, 4.9, 1H), 2.96-2.83 (m, 1H), 2.29 (s, 6H),2.15 (d, J=18.1, 3H).

Example 268:2-(5-(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N,N,6-trimethylpyrimidine-4-carboxamide

The title compound was prepared using Example 265 in a manner analogousto Example 15 substituting dimethylamine for2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole and EDClfor HATU in the last step. MS (ESI): mass calculated for C₂₃H₂₅FN₈O₂,464.21. m/z found 464.4[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 7.90-7.79 (m,2H), 7.73 (s, 1H), 7.53-7.41 (m, 1H), 7.18-7.09 (m, 1H), 6.57 (d, J=9.8,1H), 4.05-3.48 (m, 8H), 3.31-2.91 (m, 10H), 2.38 (s, 4H), 1.60 (s, 3H).

Example 269:2-(5-(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-N,N-dimethyl-4-(trifluoromethyl)pyrimidine-5-carboxamide

The title compound was prepared using Example 263 in a manner analogousto Example 15 substituting dimethylamine for2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole and EDClfor HATU in the last step. MS (ESI): mass calculated for C₂₃H₂₂F₄NO₂,518.18. m/z found 518.2 [M+H]⁺.

Example 270:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(mesityl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 23 and 2,4,6-trimethylbenzoic acid. MS (ESI):mass calculated for C₂₂H₂₈N₄O, 364.23. m/z found 365.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 6.82 (d, J=8.5, 2H), 6.29 (s, 1H), 4.03-3.29 (m, 8H),3.11-2.89 (m, 2H), 2.35-2.11 (m, 15H).

Example 271:(2,3-Difluorophenyl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 23 and 2,3-difluorobenzoic acid. MS (ESI): masscalculated for C₁₉H₂₀F₂N₄O, 358.16. m/z found 358.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 7.26-7.08 (m, 3H), 6.30 (s, 1H), 4.03-3.73 (m, 3H),3.71-3.57 (m, 3H), 3.39 (dd, J=11.3, 5.0, 2H), 3.16-2.95 (m, 2H),2.36-2.19 (m, 6H).

Example 272:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(pyrimidin-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 15substituting Intermediate 88 for 3-fluoro-2-[1,2,3]triazol-2-yl-benzoicacid. MS (ESI) mass calcd. for C₂₄H₂₆N₆O₂, 430.5. m/z found, 431.3[M+H]⁺. ¹H NMR (400 MHz, CDCl3): 8.78 (t, J=4.6 Hz, 2H), 7.80 (d, J=2.6Hz, 1H), 7.33-7.27 (m, 1H), 7.16 (q, J=4.7 Hz, 1H), 7.05 (dd, J=8.4, 2.7Hz, 1H), 6.30 (s, 1H), 3.91 (d, J=3.6 Hz, 3H), 3.85 (ddd, J=11.7, 7.8,3.4 Hz, 2H), 3.72-3.60 (m, 3H), 3.54 (dd, J=11.6, 4.8 Hz, 1H), 3.47 (dd,J=11.0, 7.3 Hz, 1H), 3.16 (dd, J=11.1, 4.9 Hz, 1H), 3.00-2.87 (m, 2H),2.30 (s, 6H).

Example 273:(2,3-Dimethoxyphenyl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 23 and 2,3-dimethoxybenzoic acid. MS (ESI): masscalculated for C₂₁H₂₆N₄O₃, 382.20. m/z found 383.4 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 7.09 (dd, J=17.8, 9.7, 1H), 6.89 (dd, J=7.9, 1.4, 2H),6.33-6.19 (m, 1H), 4.02-3.43 (m, 13H), 3.32-2.83 (m, 3H), 2.39-2.21 (m,6H).

Example 274:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(trifluoromethoxy)phenyl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 23 and 2-(trifluoromethoxy)benzoic acid. MS(ESI): mass calculated for C₂₀H₂₁F₃N₄O₂, 406.16. m/z found 407.2 [M+H]⁺.¹H NMR (400 MHz, CDCl₃): 7.49-7.27 (m, 4H), 6.30 (s, 1H), 4.08-3.36 (m,8H), 3.28-2.80 (m, 3H), 2.40-2.19 (m, 6H).

Example 275:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(6-methyl-2-[1,2,3]triazol-2-yl-pyridin-3-yl)-methanone

To a pale yellow solution of2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole(Intermediate 23) (50 mg, 0.23 mmol) in 2 mL of DMF was added6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid (Intermediate 70) (51 mg,0.25 mmol) followed by HATU (131 mg, 0.34 mmol) and DIPEA (0.118 mL,0.69 mmol). The resulting solution was allowed to stir at room temp for1 h and turned progressively more intense yellow as the reactioncontinued. The reaction was monitored via LCMS and quenched with H₂Oonce starting materials we no longer observed. The resulting biphasicmixture was extracted with EtOAc three times. The combined organiclayers were washed with brine, dried with Na₂SO₄ and conc. into a paleyellow oil under reduced pressure. The yellow residue was purified viaFCC using 5-50% 2M NH₃/MeOH in DCM. Minor impurities remained so thematerial was further purified via HPLC 0-99% CH₃N to give the desiredproduct. MS (ESI) mass calcd. for C₂₁H₂₄N₅O, 404.47; m/z found 405.3[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) 7.80 (s, 2H), 7.72 (d, J=7.7 Hz, 1H),7.29-7.24 (m, 1H), 6.30 (s, 1H), 3.90-3.80 (m, 2H), 3.73-3.63 (m, 2H),3.59 (dd, J=11.6, 5.3 Hz, 1H), 3.47 (dd, J=11.6, 3.7 Hz, 1H), 3.33 (s,1H), 3.00 (ddd, J=38.4, 21.7, 7.2 Hz, 3H), 2.68 (s, 3H), 2.30 (s, 6H).

Example 276:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-methoxy-4-methylphenyl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 23 and 2-methoxy-4-methylbenzoic acid. MS (ESI):mass calculated for C₂₁H₂₆N₄O₂, 366.21. m/z found 367.3 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.13 (d, J=7.6, 1H), 6.77 (d, J=7.6, 1H), 6.70 (s,1H), 6.28 (s, 1H), 4.00-3.40 (m, 11H), 3.27-2.85 (m, 3H), 2.41-2.19 (m,9H).

Example 277:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-methylphenyl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 23 and 4-methoxy-2-methylbenzoic acid. MS (ESI):mass calculated for C₂₁H₂₆N₄O₂, 366.21. m/z found 367.3 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.11 (d, J=7.9, 1H), 6.77-6.67 (m, 2H), 6.29 (s, 1H),4.01-3.83 (m, 2H), 3.83-3.72 (m, 4H), 3.72-3.55 (m, 2H), 3.46 (dt,J=11.9, 6.0, 2H), 3.21-2.89 (m, 3H), 2.37-2.25 (m, 9H).

Example 278:(2,6-Difluorophenyl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-ylmethanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 23 and 2,6-difluorobenzoic acid. MS (ESI): masscalculated for C₁₉H₂₀F₂N₄O, 358.16. m/z found 359.2 [M+H]⁺. ¹H NMR (400MHz, CDCl₃): 7.34 (tt, J=8.4, 6.4, 1H), 6.93 (s, 2H), 6.30 (s, 1H),4.12-3.76 (m, 3H), 3.75-3.45 (m, 4H), 3.36-2.88 (m, 3H), 2.30 (s, 6H).

Example 279:2-[5-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6-methylpyrimidine-4-carbonitrile

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 12 and Intermediate 49. MS (ESI): mass calculatedfor C₂₁H₁₉F₂N₅O, 418.44. m/z found 419.2 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 7.91-7.80 (m, 2H), 7.75 (s, 1H), 7.55-7.42 (m, 1H), 7.15 (ddd,J=8.4, 6.6, 4.0 Hz, 1H), 6.69 (d, J=5.5 Hz, 1H), 4.07-3.46 (m, 7H),3.35-3.20 (m, 1H), 3.19-2.94 (m, 2H), 2.40 (s, 3H).

Example 280:2-[4,6-Bis(trifluoromethyl)pyrimidin-2-yl]-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

Step A: Intermediate 16 (100 mg, 0.332 mmol) was diluted with DCM (10mL) and was treated with 1,3-di-boc-2-(trifluoromethylsulfonyl)guanidine(118.2 mg, 0.302 mmol) and triethyl amine (0.046 mL, 0.332 mmol). Thereaction was stirred at room temperature overnight, then was dilutedwith DCM and water, extracted and concentrated to provide crudetert-butyl(((tert-butoxycarbonyl)imino)(5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)carbamate(165 mg) which was used as is in Step B. MS (ESI): mass calculated forC₂₆H₃₄FN₇O₅, 543.60. m/z found 544.3 [M+H]⁺.

Step B: Crude tert-butyl(((tert-butoxycarbonyl)imino)(5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methyl)carbamatewas dissolved in dioxin (8 mL) and TFA (3 mL) was added and the reactionwas stirred at room temperature overnight to form crude5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboximidamide(214 mg) as a TFA salt which was used directly in Step C.

Step C: Crude5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydro-pyrrolo[3,4-c]pyrrole-2(1H)-carboximidamide—TFAsalt (66 mg) was diluted with n-butanol (4 mL) and treated with sodiummethoxide (51.9 mg, 0.961 mmol). The reaction is heated to reflux for 1hour, then cooled and 1,1,1,5,5,5-hexafluoropentane-2,4-dione (400 mg,1.92 mmol) is added prior to re-heating the reaction to reflux for 19hours. The mixture was then cooled and concentrated, then diluted withDCM and saturated sodium bicarbonate. Extract with DCM and concentrate.Reverse phase HPLC gave the title compound (4.6 mg). MS (ESI): masscalculated for C₂₁H₁₆F₇N₇O, 515.39; m/z found 416.2 [M+H]⁺. Rotamersobserved in ¹H NMR.

Example 281:2-[5-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6-methylpyrimidin-4-ol

The title compound was prepared in a manner analogous to Example 280,substituting methyl acetoacetate for1,1,1,5,5,5-hexafluoropentane-2,4-dione in Step C. MS (ESI): masscalculated for C₂₀H₂₀FN₇O₂, 409.42. m/z found 410.2 [M+H]⁺. Rotamersobserved in ¹H NMR.

Example 282:(2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-(furan-2-yl)-6-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner analogous to Example 280,substituting 1-(furan-2-yl)butane-1,3-dione for1,1,1,5,5,5-hexafluoropentane-2,4-dione in the Step C. MS (ESI): masscalculated for C₂₄H₂₂FN₇O₂, 459.49. m/z found 460.2 [M+H]⁺. ¹H NMR verybroad peaks due to rotamers.

Example 283:2-(4,6-Dimethylpyrimidin-2-yl)-5-[(3-fluoro-2-pyrimidin-2-ylphenyl)carbonyl]octahydropyrrolo[3,4-c]pyrrole

To a mixture of2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (1.4 g,6.5 mmol), 3-fluoro-2-(pyrimidin-2-yl)benzoic acid (1.4 g, 6.5 mmol),and TEA (1.3 mL, 9.7 mmol) in DMF (32.0 mL) was added HATU (2.7 g, 7.1mmol).

After 1 h, the reaction mixture was diluted with EtOAc and washed withwater. The aqueous layer was then extracted with EtOAc (1×). Thecombined organic phases were dried (Na₂SO₄), filtered and concentratedto dryness. The crude product was purified using silica gelchromatography (0-5% MeOH in EtOAc) to yield pure title compound (1.2 g,44%). MS (ESI) mass calcd. For C₂₃H₂₃FN₆O, 418.48. m/z found 419.2[M+H]⁺. ¹H NMR (CDCl₃): 8.91-8.56 (m, 2H), 7.47-7.42 (m, 1H), 7.24-7.14(m, 3H), 6.30 (s, 1H), 3.81 (dd, J=11.6, 7.2 Hz, 1H), 3.72 (ddd, J=9.0,7.2, 2.2 Hz, 2H), 3.68-3.47 (m, 4H), 3.31 (dd, J=11.0, 4.8 Hz, 1H),3.05-2.89 (m, 2H), 2.31 (s, 6H).

Example 284:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-fluoro-2-(1H-pyrazol-5-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 283,substituting Intermediate 86 for 3-fluoro-2-(pyrimidin-2-yl)benzoicacid. MS (ESI) mass calcd. C₂₂H₂₃FN₆O, 406.47. m/z found 407.2 [M+H]⁺.¹H NMR (CDCl₃): 11.33 (s, 1H), 7.50 (m, 1H), 7.35-7.31 (m, 1H),7.21-7.08 (m, 2H), 6.64 (s, 1H), 6.28 (s, 1H), 3.82-2.71 (m, 10H), 2.30(s, 6H).

Example 285:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 283,substituting 3-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid for3-fluoro-2-(pyrimidin-2-yl)benzoic acid. MS (ESI) mass calcd.C₂₂H₂₅N₇O₂, 419.49. m/z found 420.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.74 (d,J=6.6 Hz, 2H), 7.51-7.45 (m, 1H), 7.09 (dd, J=8.4, 1.0 Hz, 1H), 7.00(dd, J=7.6, 1.1 Hz, 1H), 6.29 (s, 1H), 3.87-3.76 (m, 4H), 3.66 (ddd,J=19.8, 12.1, 7.0 Hz, 2H), 3.58-3.50 (m, 2H), 3.47-3.37 (m, 2H), 3.22(dd, J=11.0, 5.1 Hz, 1H), 2.97-2.86 (m, 2H), 2.28 (s, J=20.1 Hz, 6H).

Example 286:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-methoxy-2-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

Step A: To 3-fluoro-2-(1H-1,2,3-triazol-1-yl)benzonitrile (2.1 g, 11.2mmol) in MeOH (30 mL) was added 2 M aq. NaOH (10 mL). The reaction washeated at reflux until determined complete by HPLC then cooled to roomtemperature, acidified with 1 N aq. HCl to pH=1 and extracted with DCM(2×). The combined organics were washed with brine and dried (Na₂SO₄)resulting in a mixture of two products,3-methoxy-2-(1H-1,2,3-triazol-1-yl)benzoic acid and3-fluoro-2-(1H-1,2,3-triazol-1-yl)benzoic acid, which were used withoutfurther purification in the next step.

Step B:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-methoxy-2-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole.Example 286 was prepared in a manner analogous to Example 283, utilizinga mixture of 3-methoxy-2-(1H-1,2,3-triazol-2-yl)benzoic acid and3-fluoro-2-(1H-1,2,3-triazol-2-yl)benzoic acid in place of3-fluoro-2-(pyrimidin-2-yl)benzoic acid which gave 2 products, Example286 and Example 287. For Example 286: MS (ESI) mass calcd. C₂₂H₂₃N₇O₂,419.49. m/z found 420.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.87 (d, J=1.0 Hz, 1H),7.77 (d, J=1.0 Hz, 1H), 7.52-7.45 (m, 1H), 7.09 (dd, J=8.5, 1.0 Hz, 1H),7.00 (dd, J=7.7, 1.1 Hz, 1H), 6.29 (s, J=5.2 Hz, 1H), 3.89-3.81 (m, 4H),3.79-3.65 (m, 3H), 3.54-3.46 (m, 2H), 3.43-3.36 (m, 1H), 3.24 (dt,J=12.4, 6.1 Hz, 1H), 3.02-2.91 (m, 2H), 2.29 (s, 6H).

Example 287:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-fluoro-2-(1H-1,2,3-triazol-1-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was isolated from Step B in Example 286. MS (ESI)mass calcd. C₂₁H₂₂FN₇O, 407.45. m/z found 408.2 [M+H]⁺. ¹H NMR (CDCl₃):7.96-7.91 (m, 1H), 7.84-7.80 (m, 1H), 7.58-7.49 (m, 1H), 7.37-7.30 (m,1H), 7.26-7.23 (m, 1H), 6.29 (s, 1H), 3.88-3.85 (m, 1H), 3.80-3.71 (m,2H), 3.71-3.64 (m, 1H), 3.57-3.42 (m, 3H), 3.23 (dd, J=11.0, 5.0 Hz,1H), 3.04-2.94 (m, 2H), 2.29 (s, 6H).

Example 288:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

Step A:(5-Benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone.To a mixture of 2-benzyloctahydropyrrolo[3,4-c]pyrrole (282 mg, 1.4mmol), 4-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (306 mg, 1.4mmol), and TEA (0.21 mL, 1.5 mmol) in DMF (7.5 mL) was added HATU (583mg, 1.5 mmol). After 1 h, the reaction mixture was diluted with EtOAcand washed with water. The aqueous layer was then extracted with EtOAc(1×). The combined organics were dried (Na₂SO₄) and concentrated to givea residue. Purification via Agilent prep system (Basic) gave 327 mg(58%) of the title compound as a clear oil. ¹H NMR (CDCl₃): 7.79 (s,J=6.5 Hz, 2H), 7.50 (d, J=5.0 Hz, 1H), 7.36 (d, J=8.5 Hz, 1H), 7.34-7.21(m, 5H), 6.95 (dd, J=8.5, 2.5 Hz, 1H), 3.93 (s, 3H), 3.86-3.72 (m, 1H),3.65-3.46 (m, 3H), 3.13 (s, 1H), 2.90-2.74 (m, 2H), 2.74-2.59 (m, 2H),2.57-2.39 (m, 2H), 2.16 (dd, J=9.2, 4.2 Hz, 1H).

Step B:(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone.(5-Benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanonein EtOH (20 mL) and AcOH (1 mL) was continuously flowed through a 20 wt% Pd(OH)₂/C cartridge at a rate of 1 mL/min for 2 h at 50° C. and 50 barusing a H-cube apparatus. Then the reaction was concentrated andneutralized with 5% Na₂CO₃ (aq), and extracted with CH₂Cl₂ (3×).Combined organics and dried (Na₂SO₄) to give(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanoneas a clear oil that was used without further purification. ¹H NMR(CDCl₃): 7.83-7.80 (m, 2H), 7.50 (d, J=2.5 Hz, 1H), 7.32 (d, J=8.5 Hz,1H), 6.96 (dd, J=8.5, 2.5 Hz, 1H), 3.89 (s, 3H), 3.75-3.63 (m, 2H), 3.27(s, 1H), 3.08 (dd, J=11.9, 8.1 Hz, 1H), 2.94 (dt, J=11.4, 5.7 Hz, 2H),2.88-2.75 (m, 2H), 2.69 (dd, J=17.8, 14.3 Hz, 1H), 2.56 (dd, J=11.4, 3.9Hz, 1H).

Step C:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole.To(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone(185 mg, 0.4 mmol) in DMF (2.2 mL) was added2-chloro-4,6-dimethylpyrimidine (61 mg, 0.4 mmol). The flask was heatedto 120° C. for 18 h. The flask was allowed to cool to rt, diluted withEtOAc and washed with H₂O. The aq was back-extracted with EtOAc (1×).The combined organics were washed with brine and dried (Na₂SO₄) to givean oil. Purification via silica gel (15-75% EtOAc in hexanes) gave 175mg (97%) of the title compound. MS (ESI) mass calcd. C₂₂H₂₅N₇O₂, 419.49.m/z found 420.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.73 (s, 2H), 7.49 (d, J=7.8 Hz,1H), 7.33 (d, J=8.5 Hz, 1H), 6.95 (dd, J=8.5, 2.5 Hz, 1H), 6.29 (s, 1H),3.93-3.80 (m, 5H), 3.72-3.63 (m, 2H), 3.58 (dd, J=11.6, 5.2 Hz, 1H),3.46 (dd, J=11.6, 4.3 Hz, 1H), 3.39-3.28 (m, 1H), 3.05-2.84 (m, 3H),2.33 (s, 6H).

Example 289:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[4-methoxy-2-(1H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 283,utilizing a mixture of 4-methoxy-2-(1H-1,2,3-triazol-1-yl)benzoic acidand 4-methoxy-2-(2H-1,2,3-triazol-1-yl)benzoic acid obtained from thesynthesis of Intermediate 54. Purification of the final compounds gavethe title compound as an oil. MS (ESI) mass calcd. C₂₂H₂₅N₇O₂, 419.49.m/z found 420.2 [M+H]⁺. ¹H NMR (CDCl₃: 7.98 (s, J=2.9 Hz, 1H), 7.77 (s,J=4.1 Hz, 1H), 7.42-7.36 (m, 1H), 7.18 (d, J=2.5 Hz, 1H), 7.06 (dd,J=8.5, 2.5 Hz, 1H), 6.29 (s, 1H), 3.90 (s, J=7.6 Hz, 3H), 3.83-3.66 (m,3H), 3.50-3.42 (m, 2H), 3.30 (dd, J=11.6, 4.7 Hz, 1H), 3.22 (dd, J=11.1,7.3 Hz, 1H), 2.99-2.76 (m, 3H), 2.28 (d, J=16.2 Hz, 6H).

Example 290:2-(5-Fluoro-4-methylpyrimidin-2-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

A mixture of Intermediate 20 (86 mg, 0.30 mmol), Intermediate 55 (44 mg,0.3 mmol) and DIPEA (0.16 mL, 0.91 mmol) in ACN (1 mL) was heated in themicrowave at 200° C. for 2 h. The mixture was concentrated in vacuo andchromatography (Hex to 100% EtOAc/Hex) afforded the title compound (82mg, 69%). MS (ESI): mass calculated for C₂₀H₂₀FN₇O, 393.17, m/z found394.2 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃): 8.06 (d, J=1.7 Hz, 1H), 7.98 (d,J=8.1 Hz, 1H), 7.75 (s, 2H), 7.57-7.48 (m, 1H), 7.43 (d, J=6.2 Hz, 2H),3.93-3.77 (m, 2H), 3.74-3.60 (m, 2H), 3.59-3.51 (m, 1H), 3.46-3.33 (m,2H), 3.09-2.88 (m, 3H), 2.37 (d, J=2.5 Hz, 3H).

Example 291:2-(2-Chloro-5-fluoropyrimidin-4-yl)-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 290utilizing Intermediate 20 and substituting2,4-dichloro-5-fluoropyrimidine for Intermediate 55. MS (ESI) masscalculated for C₁₉H₁₇ClFN₇O, 413.85. m/z found, 414.2 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 8.01 (d, J=8.3 Hz, 1H), 7.90 (d, J=5.0 Hz, 1H), 7.79(s, 2H), 7.58-7.51 (m, 1H), 7.48-7.39 (m, 2H), 4.04-3.93 (m, 1H),3.92-3.70 (m, 4H), 3.68-3.59 (m, 1H), 3.46 (br s, 1H), 3.13-2.88 (m,3H).

Example 292:2-(5-Fluoropyrimidin-2-yl)-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 290substituting Intermediate 16 for Intermediate 20 and2-chloro-5-fluoropyrimidine for Intermediate 55. MS (ESI) masscalculated for C₁₉H₁₇F₂N₇O, 397.39. m/z found, 398.2. ¹H NMR (400 MHz,CDCl₃): 8.26-8.17 (m, 2H), 7.89-7.78 (m, 2H), 7.73 (s, 1H), 7.53-7.44(m, 1H), 7.19-7.10 (m, 1H), 4.02-3.45 (m, 7H), 3.30-3.23 (m, 1H),3.17-2.97 (m, 2H).

Example 293:2-(5-Fluoro-4-methylpyrimidin-2-yl)-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 290substituting Intermediate 16 for Intermediate 20. MS (ESI) masscalculated for C₂₀H₁₉F₂N₇O, 411.42. m/z found, 412.2. ¹H NMR (400 MHz,CDCl₃): 8.09-8.03 (m, 1H), 7.88-7.79 (m, 2H), 7.72 (s, 1H), 7.51-7.43(m, 1H), 7.18-7.10 (m, 1H), 4.01-3.45 (m, 7H), 3.30-3.21 (m, 1H),3.15-2.95 (m, 2H), 2.37 (d, J=2.4 Hz, 3H).

Example 294:2-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(4,5,6-trimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 290substituting Intermediate 16 for Intermediate 20 and Intermediate 56 forIntermediate 55. MS (ESI) mass calculated for C₂₂H₂₄FN₇O, 421.48. m/zfound, 422.2. ¹H NMR (500 MHz, CDCl₃): 7.88-7.79 (m, 2H), 7.72 (s, 1H),7.50-7.43 (m, 1H), 7.17-7.10 (m, 1H), 3.93-3.47 (m, 7H), 3.28-3.21 (m,1H), 3.11-2.93 (m, 2H), 2.33 (s, 6H), 2.07 (s, 3H).

Example 295:2-(4,5-Dimethylpyrimidin-2-yl)-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 290substituting Intermediate 16 for Intermediate 20 and Intermediate 57 forIntermediate 55. MS (ESI) mass calculated for C₂₁H₂₂FN₇O, 407.45. m/zfound, 408.2. ¹H NMR (400 MHz, CDCl₃): 7.99 (s, 1H), 7.89-7.78 (m, 2H),7.72 (s, 1H), 7.53-7.42 (m, 1H), 7.19-7.08 (m, 1H), 4.02-3.46 (m, 7H),3.31-3.21 (m, 1H), 3.15-2.95 (m, 2H), 2.32 (s, 3H), 2.09 (s, 3H).

Example 296:2-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(4-methoxy-6-methylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was isolated from the synthesis of Intermediate 58.MS (ESI) mass calculated for C₂₁H₂₂FN₇O₂, 423.45. m/z found, 424.0. ¹HNMR (500 MHz, CDCl₃): 7.88-7.80 (m, 2H), 7.72 (s, 1H), 7.52-7.44 (m,1H), 7.18-7.11 (m, 1H), 5.87 (d, J=4.3 Hz, 1H), 4.00-3.50 (m, 10H),3.30-3.22 (m, 1H), 3.13-2.93 (m, 2H), 2.28 (s, 3H).

Example 297:2-(4-Ethyl-6-methylpyrimidin-2-yl)-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Intermediate 55substituting Intermediate 58 for 2,4-dichloro-5-fluoropyrimidine and 1.0M EtMgBr in THE for 3.0 M MeMgBr in Et₂O. MS (ESI) mass calculated forC₂₂H₂₄FN₇O, 421.48. m/z found, 422.0. ¹H NMR (500 MHz, CDCl₃): 7.88-7.79(m, 2H), 7.71 (s, 1H), 7.51-7.43 (m, 1H), 7.18-7.11 (m, 1H), 6.29 (d,J=7.2 Hz, 1H), 4.01-3.50 (m, 7H), 3.31-3.22 (m, 1H), 3.13-2.94 (m, 2H),2.56 (q, J=7.6 Hz, 2H), 2.31 (d, J=1.6 Hz, 3H), 1.27-1.21 (m, 3H).

Example 298:2-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-[4-methyl-6-(1-methylethyl)pyrimidin-2-yl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Intermediate 55substituting Intermediate 58 for 2,4-dichloro-5-fluoropyrimidine and 2.0M iPrMgBr in THE for 3.0 M MeMgBr in Et₂O. Three products were formed inthis reaction,2-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-[4-methyl-6-(1-methylethyl)pyrimidin-2-yl]octahydropyrrolo[3,4-c]pyrrole,2-[4-methyl-6-(1-methylethyl)pyrimidin-2-yl]-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrroleand2-{[5-(1-Methylethyl)-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-[4-methyl-6-(1-methylethyl)pyrimidin-2-yl]octahydropyrrolo[3,4-c]pyrrole.MS (ESI) mass calculated for C₂₃H₂₆FN₇O, 435.51; m/z found, 436.2. ¹HNMR (400 MHz, CDCl₃): 7.89-7.79 (m, 2H), 7.72 (s, 1H), 7.52-7.43 (m,1H), 7.18-7.10 (m, 1H), 6.32-6.25 (m, 1H), 4.01-3.49 (m, 7H), 3.31-3.21(m, 1H), 3.13-2.93 (m, 2H), 2.82-2.70 (m, 1H), 2.32 (d, J=2.1 Hz, 3H),1.27-1.20 (m, 6H).

Example 299:2-[4-Methyl-6-(1-methylethyl)pyrimidin-2-yl]-5-{[2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydroyrrolo[3,4-c]pyrrole

The title compound was isolated from the synthesis of Example 298. MS(ESI) mass calculated for C₂₃H₂₇N₇O, 417.52. m/z found, 418.2. ¹H NMR(500 MHz, CDCl₃): 7.98 (d, J=8.1 Hz, 1H), 7.73 (s, 2H), 7.55-7.48 (m,1H), 7.45-7.39 (m, 2H), 6.29 (s, 1H), 3.91-3.83 (m, 2H), 3.74-3.64 (m,2H), 3.63-3.57 (m, 1H), 3.50-3.44 (m, 1H), 3.42-3.27 (m, 1H), 3.07-2.88(m, 3H), 2.81-2.59 (m, 1H), 2.31 (s, 3H), 1.25-1.21 (m, 6H).

Example 300:2-{[5-(1-Methylethyl)-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-[4-methyl-6-(1-methylethyl)pyrimidin-2-yl]octahydropyrrolo[3,4-c]pyrrol

The title compound was isolated from the synthesis of Example 298. MS(ESI) mass calculated for C₂₆H₃₃N₇O, 459.6. m/z found, 460.3. ¹H NMR(400 MHz, CDCl₃): 7.84-7.72 (m, 2H), 7.67 (s, 1H), 7.51-7.32 (m, 2H),6.32-6.25 (m, 1H), 3.92-3.31 (m, 7H), 3.16-2.70 (m, 5H), 2.31 (d, J=4.7Hz, 3H), 1.28-1.14 (m, 12H).

Example 301:2-(4-tert-Butyl-6-methylpyrimidin-2-yl)-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Intermediate 55substituting Intermediate 58 for 2,4-dichloro-5-fluoropyrimidine and 1.0M tBuMgBr in THE for 3.0 M MeMgBr in Et₂O. MS (ESI) mass calculated forC₂₄H₂₈FN₇O, 449.54. m/z found, 450.3. ¹H NMR (500 MHz, CDCl₃): 7.93-7.72(m, 3H), 7.54-7.45 (m, 1H), 7.20-7.11 (m, 1H), 6.66-6.59 (m, 1H),4.23-3.60 (m, 7H), 3.38-3.06 (m, 3H), 2.67-2.43 (m, 3H), 1.29 (s, 9H).

Example 302:2-(4-Cyclopropyl-6-methylpyrimidin-2-yl)-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Intermediate 55substituting Intermediate 58 for 2,4-dichloro-5-fluoropyrimidine and 0.5M cyclopropylmagnesium bromide in THE for 3.0 M MeMgBr in Et₂O. MS (ESI)mass calculated for C₂₃H₂₄FNO, 433.49. m/z found, 434.2. ¹H NMR (500MHz, CDCl₃): 7.87-7.80 (m, 2H), 7.71 (s, 1H), 7.51-7.43 (m, 1H),7.18-7.11 (m, 1H), 6.31-6.26 (m, 1H), 3.99-3.79 (m, 2H), 3.79-3.72 (m,1H), 3.69-3.45 (m, 4H), 3.27-3.20 (m, 1H), 3.10-2.91 (m, 2H), 2.29 (s,3H), 1.82-1.74 (m, 1H), 1.10-1.00 (m, 2H), 0.95-0.88 (m, 2H).

Example 303:2-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(4-methyl-1,3,5-triazin-2-yl)octahydropyrrolo[3,4-c]pyrrole

Step A: tert-Butyl5-(4-chloro-1,3,5-triazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.To a solution of 2,4-dichloro-1,3,5-triazine (150 mg, 0.953 mmol) in ACN(5 mL) was added a solution of Intermediate 15 (202 mg, 0.953 mmol) andDIPEA (0.33 mL, 1.91 mmol) in ACN (5 mL) at 0° C. dropwise. After 10 minthe mixture was diluted with saturated aqueous NH₄Cl solution. Theaqueous layer was then extracted with DCM and the combined organicextracts were dried over Na₂SO₄, filtered and concentrated in vacuo.Chromatography (Hexanes to 80% EtOAc/Hexanes) afforded the desiredproduct as a white solid (137 mg, 44%). MS (ESI) mass calculated forC₁₄H₂₀ClN₅O₂, 325.13. m/z found, 326.1.

Step B: tert-Butyl5-(4-methyl-1,3,5-triazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.tert-Butyl5-(4-methyl-1,3,5-triazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylatewas prepared in a manner analogous to Intermediate 55 substituting theproduct of Step A for 2,4-dichloro-5-fluoropyrimidine. MS (ESI) masscalculated for C₁₅H₂₃N₅O₂, 305.18. m/z found, 306.0.

Step C: 2-(4-Methyl-1,3,5-triazin-2-yl)octahydropyrrolo[3,4-c]pyrrole.tert-Butyl5-(4-methyl-1,3,5-triazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(43 mg, 0.142 mmol), DCM (1.4 mL) and TFA (0.71 mL) were stirred at roomtemperature for 2 h. The mixture was concentrated in vacuo and taken onto the next step without further purification.

Step D:2-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(4-methyl-1,3,5-triazin-2-yl)octahydropyrrolo[3,4-c]pyrrole.Example 303 was prepared in a manner analogous to Intermediate 59substituting the product of Step C for Intermediate 15 and Intermediate12 for 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calculatedfor C₁₉H₁₉FN₈O, 394.41. m/z found, 395.0. ¹H NMR (500 MHz, CDCl₃):8.51-8.42 (m, 1H), 7.89-7.81 (m, 2H), 7.75 (d, J=3.5 Hz, 1H), 7.54-7.45(m, 1H), 7.20-7.11 (m, 1H), 4.02-3.51 (m, 8H), 3.32-3.23 (m, 1H),3.17-3.00 (m, 2H), 2.50-2.40 (m, 3H).

Example 304:2-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-5-(4-methyl-6-morpholin-4-ylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

A mixture of Intermediate 58 (137 mg, 0.254 mmol) and morpholine (1.3mL) was stirred 14 h at room temperature. The mixture was concentratedin vacuo. Chromatography (DCM to 8% 2 M NH₃ in MeOH/DCM) afforded thedesired product as a pale yellow foam (95 mg, 78%). MS (ESI) masscalculated for C₂₄H₂₇FN₈O₂, 478.53; m/z found, 479.3. ¹H NMR (500 MHz,CDCl₃): 7.86-7.78 (m, 2H), 7.72 (s, 1H), 7.51-7.44 (m, 1H), 7.18-7.10(m, 1H), 5.77-5.72 (m, 1H), 3.99-3.47 (m, 13H), 3.28-3.21 (m, 1H),3.09-2.91 (m, 2H), 2.90-2.86 (m, 2H), 2.25 (s, 3H).

Example 305:2-{[2-(4H-1,2,4-Triazol-3-yl)phenyl]carbonyl}-5-(4,5,6-trimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

Step A:(2-(4H-1,2,4-Triazol-3-yl)phenyl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone.(2-(4H-1,2,4-Triazol-3-yl)phenyl)(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanonewas prepared in a manner analogous to Example 303, substitutingIntermediate 59 for the product of Example 303 in Step C. MS (ESI) masscalculated for C₁₅H₁₇NO, 283.14. m/z found, 284.2.

Step B:2-{[2-(4H-1,2,4-Triazol-3-yl)phenyl]carbonyl}-5-(4,5,6-trimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole.The product of Step A (167 mg, 0.421 mmol), Intermediate 56 (66 mg,0.421 mmol) and DIPEA (0.29 mL, 1.68 mmol) were heated for 2 h at 200°C. in ACN (1.4 mL) in the microwave. The mixture was concentrated invacuo. The crude product was purified using Agilent HPLC (basic system)to yield impure material. This material was subsequently purified usingnormal phase chromatography (DCM to 8% 2M NH₃ in MeOH/DCM) to afford thetitle compound (49 mg, 29%). MS (ESI) mass calculated for C₂₂H₂₅N₇O,403.49. m/z found, 404.2. ¹H NMR (500 MHz, CDCl₃): 8.16 (d, J=7.8 Hz,1H), 8.06 (s, 1H), 7.54-7.49 (m, 1H), 7.48-7.44 (m, 1H), 7.35 (d, J=7.5Hz, 1H), 3.96-3.89 (m, 1H), 3.85-3.77 (m, 1H), 3.74-3.68 (m, 1H),3.68-3.55 (m, 2H), 3.42 (br s, 2H), 3.16 (br s, 1H), 3.04-2.96 (m, 1H),2.89 (br s, 1H), 2.32 (s, 6H), 2.05 (s, 3H).

Example 306:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Intermediate 59substituting Intermediate 23 for Intermediate 15 and2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid for2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calculated forC₂₂H₂₄N₆O₂, 404.48. m/z found, 405.2. ¹H NMR (500 MHz, CDCl₃): 8.10 (dd,J=7.9 Hz, 0.9 Hz, 1H), 7.62 (td, J=7.6 Hz, 1.2 Hz, 1H), 7.53 (td, J=7.7Hz, 1.3 Hz, 1H), 7.42 (dd, J=7.6 Hz, 1.0 Hz, 1H), 6.28 (s, 1H),3.99-3.88 (m, 2H), 3.80-3.75 (m, 1H), 3.74-3.65 (m, 2H), 3.53-3.48 (m,1H), 3.46-3.40 (m, 1H), 3.12-3.04 (m, 2H), 3.01-2.93 (m, 1H), 2.42 (s,3H), 2.28 (s, 6H).

Example 307:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

Step A:(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl)methanone.Intermediate 60 (100 mg, 0.252 mmol), DCM (2.5 mL), TFA (0.5 mL) werestirred at room temperature for 2 h and then concentrated in vacuo. Theresidue was dissolved in DCM and treated with Dowex 550 A resin. Afterstirring for 2 h the resin was removed by filtration and the filtratewas concentrated in vacuo to a colorless oil which was taken on to thenext step without further purification. MS (ESI) mass calculated forC₁₆H₁₉N₅O, 297.16. m/z found, 298.0.

Step B:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-(1-methyl-1H-1,2,4-triazol-5-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole.Example 307 was prepared in a manner analogous to Example 290substituting the product of Step A for Intermediate 20 and2-chloro-4,6-dimethylpyrimidine for Intermediate 55. MS (ESI) masscalculated for C₂₂H₂₅N₇O, 403.21. m/z found, 404.2. ¹H NMR (500 MHz,CDCl₃): 7.83 (s, 1H), 7.58-7.49 (m, 2H), 7.47-7.42 (m, 2H), 6.28 (s,1H), 3.85-3.80 (m, 4H), 3.75-3.69 (m, 2H), 3.55-3.45 (m, 4H), 3.24-3.19(m, 1H), 2.99-2.88 (m, 2H), 2.29 (s, 6H).

Example 308:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 307substituting Intermediate 61 for Intermediate 60 in Step A. MS (ESI)mass calculated for C₂₂H₂₅N₇O, 403.21. m/z found, 404.2. ¹H NMR (500MHz, CDCl₃): 8.12-8.06 (m, 1H), 7.93 (s, 1H), 7.49-7.38 (m, 2H),7.37-7.29 (m, 1H), 6.27 (s, 1H), 3.95-3.83 (m, 5H), 3.78-3.60 (m, 3H),3.47-3.38 (m, 2H), 3.08-2.98 (m, 2H), 2.95-2.86 (m, 1H), 2.29 (s, 6H).

Example 309:2-{[2-(3-Methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}-5-(4,5,6-trimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 307substituting Intermediate 62 for Intermediate 60 in Step A, andIntermediate 56 for 2-chloro-4,6-dimethylpyrimidine in Step B. MS (ESI)mass calculated for C₂₃H₂₆N₆O₂, 418.21. m/z found, 419.3. ¹H NMR (500MHz, CDCl₃): 8.09 (dd, J=7.9 Hz, 0.9 Hz, 1H), 7.60 (td, J=7.6 Hz, 1.2Hz, 1H), 7.52 (td, J=7.7 Hz, 1.3 Hz, 1H), 7.41 (dd, J=7.6 Hz, 1.0 Hz,1H), 3.98-3.93 (m, 1H), 3.90-3.84 (m, 1H), 3.79-3.73 (m, 1H), 3.70-3.61(m, 2H), 3.50-3.44 (m, 1H), 3.44-3.38 (m, 1H), 3.10-3.02 (m, 2H),2.98-2.91 (m, 1H), 2.42 (s, 3H), 2.30 (s, 6H), 2.06 (s, 3H).

Example 310:2-(5-Fluoro-4-methylpyrimidin-2-yl)-5-{[2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 307substituting Intermediate 62 for Intermediate 60 in Step A, andIntermediate 55 for 2-chloro-4,6-dimethylpyrimidine in Step B. MS (ESI)mass calculated for C₂₁H₂₁FN₆O₂, 408.17. m/z found, 409.2. ¹H NMR (500MHz, CDCl₃): 8.10 (dd, J=7.9 Hz, 0.9 Hz, 1H), 8.04 (d, J=1.8 Hz, 1H),7.61 (td, J=7.6 Hz, 1.3 Hz, 1H), 7.53 (td, J=7.7 Hz, 1.3 Hz, 1H), 7.42(dd, J=7.6 Hz, 1.0 Hz, 1H), 4.00-3.94 (m, 1H), 3.90-3.83 (m, 1H),3.79-3.74 (m, 1H), 3.71-3.60 (m, 2H), 3.47-3.41 (m, 2H), 3.13-3.06 (m,2H), 3.02-2.94 (m, 1H), 2.41 (s, 3H), 2.35 (d, J=2.5 Hz, 3H).

Example 311:2-{[2-(1-Methyl-1H-1,2,4-triazol-3-yl)phenyl]carbonyl}-5-(4,5,6-trimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 307substituting Intermediate 61 for Intermediate 60 in Step A, andIntermediate 56 for 2-chloro-4,6-dimethylpyrimidine in Step B. MS (ESI)mass calculated for C₂₃H₂₇N₇O, 417.23. m/z found, 418.2. ¹H NMR (500MHz, CDCl₃): 8.11-8.04 (m, 1H), 7.93 (s, 1H), 7.47-7.38 (m, 2H),7.34-7.30 (m, 1H), 3.94-3.79 (m, 5H), 3.75-3.69 (m, 1H), 3.66-3.56 (m,2H), 3.43-3.36 (m, 2H), 3.07-2.97 (m, 2H), 2.92-2.85 (m, 1H), 2.32 (s,6H), 2.06 (s, 3H).

Example 312:2-(5-Fluoro-4-methylpyrimidin-2-yl)-5-{[2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 307substituting Intermediate 61 for Intermediate 60 in Step A, andIntermediate 55 for 2-chloro-4,6-dimethylpyrimidine in Step B. MS (ESI)mass calculated for C₂₁H₂₂FN₇O, 407.19. m/z found, 408.2. ¹H NMR (500MHz, CDCl₃): 8.09 (dd, J=7.5 Hz, 1.5 Hz, 1H), 8.04 (d, J=1.7 Hz, 1H),7.94 (s, 1H), 7.47-7.39 (m, 2H), 7.34-7.30 (m, 1H), 3.97-3.85 (m, 4H),3.85-3.78 (m, 1H), 3.76-3.70 (m, 1H), 3.66-3.55 (m, 2H), 3.45-3.36 (m,2H), 3.09-3.00 (m, 2H), 2.97-2.88 (m, 1H), 2.35 (d, J=2.5 Hz, 3H).

Example 313:2-[5-{[2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

The title compound was prepared in a manner analogous to Example 290substituting Intermediate 16 for Intermediate 20 and2-chloro-4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine forIntermediate 55. MS (ESI) mass calculated for C₂₃H₂₄FN₇O, 433.20. m/zfound, 434.2. 1H NMR (500 MHz, CDCl₃): 7.87-7.78 (m, 2H), 7.72 (s, 1H),7.49-7.42 (m, 1H), 7.17-7.09 (m, 1H), 4.01-3.84 (m, 2H), 3.82-3.49 (m,5H), 3.29-3.22 (m, 1H), 3.13-2.93 (m, 2H), 2.86-2.79 (m, 2H), 2.78-2.72(m, 2H), 2.28 (s, 3H), 2.09-2.00 (m, 2H).

Example 314:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Intermediate 59substituting Intermediate 23 for Intermediate 15 and Intermediate 63 for2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calculated forC₂₂H₂₃FN₆O₂, 422.19. m/z found, 423.2. ¹H NMR (500 MHz, CDCl₃):7.62-7.56 (m, 1H), 7.31-7.26 (m, 1H), 7.24-7.20 (m, 1H), 6.29 (s, 1H),3.93-3.86 (m, 2H), 3.77-3.62 (m, 3H), 3.57-3.47 (m, 2H), 3.21-3.16 (m,1H), 3.10-2.96 (m, 2H), 2.43 (s, 3H), 2.28 (s, 6H).

Example 315:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[2-fluoro-6-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Intermediate 59substituting Intermediate 23 for Intermediate 15 and Intermediate 64 for2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calculated forC₂₂H₂₃FN₆O₂, 422.19. m/z found, 423.2. ¹H NMR (500 MHz, CDCl₃):7.96-7.86 (m, 1H), 7.55-7.47 (m, 1H), 7.38-7.29 (m, 1H), 6.32-6.23 (m,1H), 3.99-3.46 (m, 7H), 3.27-2.95 (m, 3H), 2.49-2.37 (m, 3H), 2.36-2.21(m, 6H).

Example 316:2-(5-Chloro-4-methylpyrimidin-2-yl)-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 290substituting Intermediate 16 for Intermediate 20 and Intermediate 65 forIntermediate 55. MS (ESI) mass calculated for C₂₀H₁₉ClFN₇O, 427.13. m/zfound, 428.1. 1H NMR (500 MHz, CDCl₃): 8.13 (d, J=1.3 Hz, 1H), 7.87-7.79(m, 2H), 7.71 (s, 1H), 7.51-7.43 (m, 1H), 7.17-7.11 (m, 1H), 4.00-3.54(m, 7H), 3.28-3.23 (m, 1H), 3.14-2.97 (m, 2H), 2.43 (s, 3H).

Example 317:2-(5-Chloro-4,6-dimethylpyrimidin-2-yl)-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 290substituting Intermediate 16 for Intermediate 20 and Intermediate 66 forIntermediate 55. MS (ESI) mass calculated for C₂₁H₂₁ClFN₇O, 441.15. m/zfound, 442.1. 1H NMR (500 MHz, CDCl₃): 7.87-7.79 (m, 2H), 7.71 (s, 1H),7.50-7.44 (m, 1H), 7.17-7.11 (m, 1H), 4.00-3.73 (m, 3H), 3.70-3.46 (m,4H), 3.27-3.22 (m, 1H), 3.12-2.94 (m, 2H), 2.42 (s, 6H).

Example 318:2-(5-Chloro-4,6-dimethylpyrimidin-2-yl)-5-{[2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 307substituting Intermediate 62 for Intermediate 60 in Step A, andIntermediate 66 for 2-chloro-4,6-dimethylpyrimidine in Step B. MS (ESI)mass calculated for C₂₂H₂₃ClN₆O₂, 438.16. m/z found, 439.2. 1H NMR (500MHz, CDCl₃): 8.11 (dd, J=7.6 Hz, 1.2 Hz, 1H), 7.62 (td, J=7.6 Hz, 1.2Hz, 1H), 7.54 (td, J=7.6 Hz, 1.2 Hz, 1H), 7.42 (dd, J=7.6 Hz, 1.2 Hz,1H), 3.99-3.92 (m, 1H), 3.90-3.84 (m, 1H), 3.80-3.74 (m, 1H), 3.70-3.61(m, 2H), 3.50-3.41 (m, 2H), 3.12-3.04 (m, 2H), 3.02-2.94 (m, 1H),2.46-2.36 (m, 9H).

Example 319:4-Methyl-2-[5-{[2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]-6,7-dihydro-5H-cyclopenta[d]pyrimidine

The title compound was prepared in a manner analogous to Example 307substituting Intermediate 62 for Intermediate 60 in Step A, and2-chloro-4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine for2-chloro-4,6-dimethylpyrimidine in Step B. MS (ESI) mass calculated forC₂₄H₂₆N₆O₂, 430.21. m/z found, 431.2. ¹H NMR (500 MHz, CDCl₃): 8.10 (dd,J=7.9 Hz, 0.9 Hz, 1H), 7.61 (td, J=7.6 Hz, 1.3 Hz, 1H), 7.53 (td, J=7.6Hz, 1.3 Hz, 1H), 7.42 (dd, J=7.6 Hz, 1.0 Hz, 1H), 3.99-3.87 (m, 2H),3.80-3.74 (m, 1H), 3.73-3.65 (m, 2H), 3.52-3.47 (m, 1H), 3.45-3.39 (m,1H), 3.11-3.05 (m, 2H), 3.01-2.93 (m, 1H), 2.83-2.72 (m, 4H), 2.43 (s,3H), 2.26 (s, 3H), 2.08-2.00 (m, 2H).

Example 320:2-(5-Chloro-4,6-dimethylpyrimidin-2-yl)-5-{[2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 307substituting Intermediate 61 for Intermediate 60 in Step A, andIntermediate 66 for 2-chloro-4,6-dimethylpyrimidine in Step B. MS (ESI)mass calculated for C₂₂H₂₄ClN₇O, 437.17. m/z found, 438.2. ¹H NMR (500MHz, CDCl₃): 8.12-8.06 (m, 1H), 7.95 (s, 1H), 7.47-7.40 (m, 2H),7.34-7.31 (m, 1H), 3.96-3.85 (m, 4H), 3.85-3.78 (m, 1H), 3.77-3.70 (m,1H), 3.65-3.57 (m, 2H), 3.45-3.38 (m, 2H), 3.08-3.00 (m, 2H), 2.95-2.87(m, 1H), 2.41 (s, 6H).

Example 321:2-(5-Chloro-4-methylpyrimidin-2-yl)-5-{[2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 307substituting Intermediate 61 for Intermediate 60 in Step A, andIntermediate 65 for 2-chloro-4,6-dimethylpyrimidine in Step B. MS (ESI)mass calculated for C₂₁H₂₂ClN₇O, 423.16. m/z found, 424.2. ¹H NMR (500MHz, CDCl₃): 8.15-8.06 (m, 2H), 7.96 (s, 1H), 7.48-7.40 (m, 2H),7.36-7.30 (m, 1H), 3.96-3.80 (m, 5H), 3.79-3.70 (m, 1H), 3.67-3.55 (m,2H), 3.47-3.37 (m, 2H), 3.10-3.01 (m, 2H), 2.99-2.90 (m, 1H), 2.41 (s,3H).

Example 322:2-(5-Ethyl-4,6-dimethylpyrimidin-2-yl)-5-{[2-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 307substituting Intermediate 61 for Intermediate 60 in Step A, andIntermediate 67 for 2-chloro-4,6-dimethylpyrimidine in Step B. MS (ESI)mass calculated for C₂₄H₂₉N₇O, 431.24. m/z found, 432.2. ¹H NMR (500MHz, CDCl₃): 8.11-8.05 (m, 1H), 7.95 (s, 1H), 7.48-7.39 (m, 2H),7.35-7.30 (m, 1H), 3.96-3.79 (m, 5H), 3.77-3.70 (m, 1H), 3.66-3.55 (m,2H), 3.43-3.35 (m, 2H), 3.08-2.97 (m, 2H), 2.94-2.86 (m, 1H), 2.52 (q,J=7.5 Hz, 2H), 2.34 (s, 6H), 1.08 (t, J=7.5 Hz, 3H).

Example 323:2-{[3-(2H-1,2,3-Triazol-2-yl)pyridin-2-yl]carbonyl}-5-(4,5,6-trimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 290substituting Intermediate 68 for Intermediate 20 and Intermediate 56 forIntermediate 55. MS (ESI) mass calculated for C₂₁H₂₄N₅O, 404.21. m/zfound, 405.2. ¹H NMR (500 MHz, CDCl₃): 8.62 (dd, J=4.7 Hz, 1.4 Hz, 1H),8.33 (dd, J=8.3 Hz, 1.4 Hz, 1H), 7.79 (s, 2H), 7.48 (dd, J=8.3 Hz, 4.7Hz, 1H), 3.96-3.84 (m, 2H), 3.78-3.63 (m, 4H), 3.60-3.54 (m, 1H),3.29-3.23 (m, 1H), 3.12-2.98 (m, 2H), 2.33 (s, 6H), 2.07 (s, 3H).

Example 324:2-(5-Chloro-4,6-dimethylpyrimidin-2-yl)-5-{[3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 290substituting Intermediate 68 for Intermediate 20 and Intermediate 66 forIntermediate 55. MS (ESI) mass calculated for C₂₀H₂₁ClN₈O, 424.15. m/zfound, 425.1. ¹H NMR (500 MHz, CDCl₃): 8.62 (dd, J=4.7 Hz, 1.4 Hz, 1H),8.33 (dd, J=8.3 Hz, 1.4 Hz, 1H), 7.81 (s, 2H), 7.48 (dd, J=8.3 Hz, 4.7Hz, 1H), 3.95-3.89 (m, 1H), 3.89-3.83 (m, 1H), 3.79-3.74 (m, 1H),3.73-3.64 (m, 3H), 3.60-3.53 (m, 1H), 3.28-3.23 (m, 1H), 3.13-2.98 (m,2H), 2.42 (s, 6H).

Example 325:2-(5-Fluoro-4,6-dimethylpyrimidin-2-yl)-5-{[3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 290substituting Intermediate 68 for Intermediate 20 and Intermediate 69 forIntermediate 55. MS (ESI) mass calculated for C₂₀H₂₁FN₈O, 408.18. m/zfound, 409.1. ¹H NMR (500 MHz, CDCl₃): 8.62 (dd, J=4.7 Hz, 1.4 Hz, 1H),8.34 (dd, J=8.3 Hz, 1.4 Hz, 1H), 7.79 (s, 2H), 7.48 (dd, J=8.3 Hz, 4.7Hz, 1H), 3.97-3.89 (m, 1H), 3.88-3.82 (m, 1H), 3.78-3.73 (m, 1H),3.72-3.62 (m, 3H), 3.57-3.51 (m, 1H), 3.29-3.23 (m, 1H), 3.12-2.99 (m,2H), 2.33 (d, J=2.6 Hz, 6H).

Example 326:2-(4,6-Dimethylpyrimidin-2-yl)-5-(9H-fluoren-4-ylcarbonyl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15substituting 9H-fluorene-4-carboxylic acid for3-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid. MS (ESI) mass calculatedfor C₂₀H₂₁FN₈O, 410.52. m/z found, 411.2. ¹H NMR (400 MHz, CDCl₃):7.68-7.61 (m, 1H), 7.58-7.51 (m, 2H), 7.35-7.23 (m, 4H), 6.28 (s, 1H),4.13 (dd, J=12.8, 7.9 Hz, 1H), 3.94-3.87 (m, 3H), 3.80 (dd, J=12.8, 5.0Hz, 1H), 3.73-3.64 (m, 2H), 3.46 (s, 2H), 3.11 (dtd, J=12.5, 7.5, 4.9Hz, 2H), 2.97-2.86 (m, 1H), 2.28 (s, 6H).

Example 327:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(5-[1,2,3]triazol-2-yl-benzo[1,3]dioxol-4-yl)-methanone

The title compound was prepared in a manner analogous to Example 275substituting 5-[1,2,3]triazol-2-yl-benzo[1,3]dioxole-4-carboxylic acid(Intermediate 76) for 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS(ESI) mass calcd. for C₂₂H₂₃N₇O₃, 433.47. m/z found 434.3 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.75 (s, 1H), 7.64 (s, 1H), 7.42 (t, J=8.7 Hz, 1H),6.89 (d, J=8.5 Hz, 1H), 6.29 (d, J=3.4 Hz, 1H), 6.13-5.99 (m, 2H),3.95-3.75 (m, 3H), 3.74-3.50 (m, 5H), 3.26 (ddd, J=43.0, 10.7, 5.1 Hz,1H), 3.09-2.92 (m, 2H), 2.30 (s, 6H).

Example 328:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(8-[1,2,3]triazol-2-yl-naphthalen-1-yl)-methanone

The title compound was prepared in a manner analogous to Example 275substituting 8-[1,2,3]triazol-2-yl-naphthalene-1-carboxylic acid(Intermediate 75) for 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS(ESI) mass calcd. for C₂H₂₅N₇O, 439.41; m/z found 440.3 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) 8.00 (m, J=11.0, 7.1, 2.7 Hz, 2H), 7.80 (m, J=51.6 Hz,2H), 7.69-7.49 (m, 4H), 6.31 (m, J=12.7 Hz, 1H), 3.91 (m, J=11.6, 7.7Hz, 1H), 3.85-3.62 (m, 4H), 3.57-3.47 (m, 2H), 3.38-3.28 (m, 1H), 3.18(m, J=10.9, 5.9 Hz, 1H), 3.06-2.93 (m, 2H), 2.30 (m, J=8.3 Hz, 6H).

Example 329:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(4-[1,2,3]triazol-1-yl-pyridin-3-yl)-methanone

The title compound was prepared in a manner analogous to Example 275substituting 4-(1H-1,2,3-triazol-1-yl)nicotinic acid (Intermediate 81)for 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI) mass calcd.for C₂₀H₂₂N₈O, 390.40. m/z found 391.4 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):8.83 (d, J=5.4 Hz, 1H), 8.75 (s, 1H), 8.10 (d, J=1.0 Hz, 1H), 7.82 (d,J=0.9 Hz, 1H), 7.69 (d, J=5.4 Hz, 1H), 6.31 (s, 1H), 3.86 (ddd, J=16.6,12.3, 7.7 Hz, 2H), 3.75-3.67 (m, 1H), 3.56 (ddd, J=16.5, 12.3, 4.8 Hz,2H), 3.35 (dt, J=14.9, 7.7 Hz, 2H), 3.04-2.86 (m, 3H), 2.30 (s, 6H).

Example 330:(5-tert-Butyl-2-methoxy-phenyl)-[5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 275substituting 5-tert-butyl-2-methoxybenzoic acid for6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI) mass calcd. forC₂₄H₃₂N₄O₂, 408.54. m/z found 409.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.34 (dd, J=8.7, 2.5 Hz, 1H), 7.27-7.24 (m, 1H), 6.82 (d, J=8.7 Hz, 1H),6.29 (s, 1H), 3.96 (dd, J=12.7, 7.9 Hz, 1H), 3.87 (dd, J=11.6, 7.4 Hz,1H), 3.80-3.73 (m, 4H), 3.67-3.60 (m, 2H), 3.57-3.45 (m, 2H), 3.21 (dd,J=11.0, 4.7 Hz, 1H), 3.09-3.00 (m, 1H), 2.99-2.91 (m, 1H), 2.29 (s, 6H),1.28 (s, 9H).

Example 331:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(1-[1,2,3]triazol-2-yl-naphthalen-2-yl)-methanone

The title compound was prepared in a manner analogous to Example 275substituting 1-[1,2,3]triazol-2-yl-naphthalene-2-carboxylic acid(Intermediate 73) for 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS(ESI) mass calcd. for C₂₅H₂₅N₇O, 439.52. m/z found 440.3 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 8.02 (d, J=8.4 Hz, 1H), 7.95-7.91 (m, 1H), 7.88 (s,2H), 7.72 (d, J=8.3 Hz, 1H), 7.56 (dddd, J=14.9, 8.2, 6.9, 1.3 Hz, 2H),7.52-7.48 (m, 1H), 6.30 (s, 1H), 3.83 (dd, J=11.6, 7.5 Hz, 1H), 3.72(ddd, J=14.6, 12.2, 7.1 Hz, 2H), 3.56-3.45 (m, 4H), 3.19 (dd, J=11.0,5.4 Hz, 1H), 3.00-2.87 (m, 3H), 2.31 (s, 6H).

Example 332:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(3-[1,2,3]triazol-2-yl-pyridin-2-yl)-methanone

The title compound was prepared in a manner analogous to Example 275substituting 3-[1,2,3]triazol-2-yl-pyridine-2-carboxylic acid(Intermediate 72) for 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid.Excess amounts of acetic acid from the purification of the acid (inprevious steps) still remained and allowed the acetamide to be formed insignificant quantities as a byproduct, which was isolated in addition tothe title compound. MS (ESI) mass calcd. for C₂₀H₂₂N₅O, 390.44. m/zfound 391.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.62 (dd, J=4.7, 1.3 Hz,1H), 8.33 (dd, J=8.3, 1.3 Hz, 1H), 7.79 (s, 2H), 7.48 (dd, J=8.3, 4.7Hz, 1H), 6.28 (s, 1H), 3.92 (td, J=12.5, 7.4 Hz, 2H), 3.80-3.57 (m, 5H),3.26 (dd, J=10.8, 5.3 Hz, 1H), 3.12-2.98 (m, 2H), 2.30 (s, 6H).

Example 333:(2-Bromo-4,5-dimethoxy-phenyl)-[5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 275substituting 5-acetamido-2-bromobenzoic acid for6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI) mass calcd. forC₂₁H₂₅BrN₄O₃, 461.35. m/z found 463.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):6.98 (s, 1H), 6.77 (s, 1H), 6.30 (s, 1H), 3.98-3.89 (m, 2H), 3.86 (d,J=9.2 Hz, 6H), 3.79 (dd, J=11.6, 7.2 Hz, 1H), 3.67-3.59 (m, 2H), 3.53(dd, J=11.5, 4.4 Hz, 2H), 3.22 (s, 1H), 3.12-2.96 (m, 2H), 2.29 (s, 6H).

Example 334:(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-6-yl)-[5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 275substituting 3,4-dihydro-2H-1,5-benzodioxepine-6-carboxylic acid for6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI) mass calcd. forC₂₂H₂₆N₄O₃, 394.47; m/z found 395.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):6.99 (dd, J=7.9, 1.9 Hz, 1H), 6.93 (t, J=7.6 Hz, 1H), 6.88 (dd, J=7.4,1.9 Hz, 1H), 6.29 (s, 1H), 4.20 (s, 2H), 3.90 (ddd, J=19.1, 12.1, 7.6Hz, 2H), 3.81-3.73 (m, 1H), 3.68-3.58 (m, 2H), 3.57-3.45 (m, 2H), 3.23(dd, J=10.9, 4.7 Hz, 1H), 3.09-2.90 (m, 2H), 2.29 (s, 6H), 2.14 (d,J=5.9 Hz, 2H).

Example 335:(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-fluoro-2-(6-methylpyridin-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 248,substituting 6-methyl-2-(tributylstannyl)pyridine for5-methyl-2-(tributylstannyl)pyridine. MS (ESI) mass calcd. forC₂₅H₂₆FN₅O, 431.21; found 432.2 [M+H]⁺.

Example 336:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(6-methyl-2-[1,2,3]triazol-1-yl-pyridin-3-yl)-methanone

The title compound was prepared in a manner analogous to Example 275substituting 6-methyl-2-[1,2,3]triazol-1-yl-nicotinic acid (Intermediate71) for 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI) masscalcd. for C₂₁H₂₄N₈O, 404.47; m/z found 405.3 [M+H]⁺. ¹H NMR (400 MHz,CDCl₃): 8.45 (d, J=0.7 Hz, 1H), 7.78 (s, 1H), 7.71 (d, J=7.7 Hz, 1H),7.26 (t, J=3.9 Hz, 1H), 6.29 (s, 1H), 4.01 (dd, J=12.6, 7.7 Hz, 1H),3.91 (dd, J=11.6, 7.7 Hz, 1H), 3.76 (dd, J=11.6, 7.2 Hz, 1H), 3.65-3.58(m, 2H), 3.51 (ddd, J=16.0, 11.1, 5.9 Hz, 2H), 3.15 (dt, J=10.1, 5.1 Hz,1H), 3.12-2.95 (m, 2H), 2.61 (s, 3H), 2.30 (s, 6H).

Example 337:(1-Bromo-naphthalen-2-yl)-[5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 275substituting 5-acetamido-2-bromobenzoic acid for6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI) mass calcd. forC₂₃H₂₃BrN₄O, 451.36. m/z found 451.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):8.29 (d, J=7.1 Hz, 1H), 7.85 (t, J=7.5 Hz, 2H), 7.64 (t, J=7.4 Hz, 1H),7.60-7.54 (m, 1H), 7.33 (s, 1H), 6.30 (s, 1H), 4.03 (s, 1H), 3.91 (s,1H), 3.77 (dt, J=14.9, 7.4 Hz, 2H), 3.66 (dd, J=11.6, 5.0 Hz, 1H), 3.51(d, J=52.5 Hz, 2H), 3.18 (d, J=65.6 Hz, 2H), 2.98 (d, J=21.2 Hz, 1H),2.30 (s, 6H).

Example 338:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(3-methoxy-naphthalen-2-yl)-methanone

The title compound was prepared in a manner analogous to Example 275substituting 3-methoxy-2-naphthoic acid for6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI) mass calcd. forC₂₄H₂₆N₄O₂, 402.49. m/z found 403.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):7.78-7.70 (m, 3H), 7.49-7.43 (m, 1H), 7.39-7.32 (m, 1H), 7.15 (s, 1H),6.29 (s, 1H), 3.99 (dd, J=12.7, 7.9 Hz, 1H), 3.93-3.85 (m, 4H),3.79-3.62 (m, 3H), 3.56-3.45 (m, 2H), 3.21 (dd, J=11.1, 4.9 Hz, 1H),3.11-3.02 (m, 1H), 2.99-2.90 (m, 1H), 2.30 (s, 6H).

Example 339:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(8-[1,2,3]triazol-2-yl-naphthalen-1-yl)-methanone

The title compound was prepared in a manner analogous to Example 275substituting 1-[1,2,3]triazol-1-yl-naphthalene-2-carboxylic acid(Intermediate 74) for 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS(ESI) mass calcd. for C₂₅H₂₅N₇O, 439.52. m/z found 440.3 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 8.08 (d, J=8.4 Hz, 1H), 8.01 (d, J=0.8 Hz, 1H), 7.97(d, J=8.0 Hz, 1H), 7.92 (d, J=0.8 Hz, 1H), 7.65-7.59 (m, 1H), 7.56 (ddd,J=8.1, 7.0, 1.2 Hz, 1H), 7.51-7.47 (m, 1H), 7.36 (d, J=8.4 Hz, 1H), 6.29(s, 1H), 3.82 (dd, J=11.6, 7.3 Hz, 1H), 3.76-3.63 (m, 2H), 3.56 (dd,J=11.2, 7.1 Hz, 1H), 3.49 (dd, J=11.5, 3.8 Hz, 1H), 3.45-3.36 (m, 2H),3.14 (dd, J=11.2, 4.9 Hz, 1H), 2.96-2.84 (m, 2H), 2.29 (s, 6H).

Example 340:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(1-methoxy-naphthalen-2-yl)-methanone

The title compound was prepared in a manner analogous to Example 275substituting 1-methoxy-2-naphthoic acid for6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS (ESI) mass calcd. forC₂₄H₂₆N₄O₂, 402.49. m/z found 403.3 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃):8.19-8.12 (m, 1H), 7.84 (dt, J=6.2, 2.6 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H),7.56-7.49 (m, 2H), 7.36 (d, J=8.4 Hz, 1H), 6.30 (s, 1H), 4.07-3.97 (m,4H), 3.91 (dd, J=11.5, 7.5 Hz, 1H), 3.80-3.55 (m, 4H), 3.48 (dd, J=11.5,4.6 Hz, 1H), 3.33 (s, 1H), 3.13-3.04 (m, 1H), 3.01-2.92 (m, 1H), 2.30(s, 6H).

Example 341:(4,5-Dimethoxy-2-[1,2,3]triazol-1-yl-phenyl)-[5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 275substituting 2,3-dimethoxy-6-[1,2,3]triazol-1-yl-benzoic acid(Intermediate 78) for 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS(ESI) mass calcd. for C₂₃H₂₇N₇O₃, 449.51. m/z found 450.3 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.93 (s, 1H), 7.77 (s, 1H), 7.17 (s, 1H), 6.92 (s,1H), 6.29 (s, 1H), 3.95 (d, J=1.6 Hz, 6H), 3.74 (ddd, J=29.3, 15.1, 7.9Hz, 3H), 3.46 (d, J=8.6 Hz, 2H), 3.28 (d, J=7.5 Hz, 1H), 3.14 (d, J=7.4Hz, 1H), 2.89 (s, 2H), 2.77 (d, J=6.0 Hz, 1H), 2.29 (s, 6H).

Example 342:(4,5-Dimethoxy-2-[1,2,3]triazol-2-yl-phenyl)-[5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-methanone

The title compound was prepared in a manner analogous to Example 275substituting 2,3-dimethoxy-6-[1,2,3]triazol-2-yl-benzoic acid(Intermediate 77) for 6-methyl-2-[1,2,3]triazol-2-yl-nicotinic acid. MS(ESI) mass calcd. for C₂₃H₂₇N₇O₃, 449.51; m/z found 450.3 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃): 7.70 (s, 2H), 7.45 (s, 1H), 6.89 (s, 1H), 6.29 (s,1H), 3.97 (s, 3H), 3.93 (s, 3H), 3.84 (dt, J=11.6, 7.6 Hz, 2H), 3.65(dd, J=12.5, 4.1 Hz, 2H), 3.55 (dd, J=11.5, 5.2 Hz, 1H), 3.44 (dd,J=11.6, 3.8 Hz, 1H), 3.27 (s, 1H), 3.03-2.93 (m, 1H), 2.85 (d, J=24.5Hz, 2H), 2.30 (s, 6H).

Example 343:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-fluoro-2-(4-methylpyridin-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 248substituting 4-methyl-2-(tributylstannyl)pyridine for5-methyl-2-(tributylstannyl)pyridine. MS (ESI) mass calcd. forC₂₅H₂₆FN₅O, 431.21. m/z found 432.2 [M+H]⁺.

Example 344:(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-propoxypyridin-2-yl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 23 and 2-propoxynicotinic acid. MS (ESI) masscalcd. C₂₁H₂₇N₅O₂, 381.48. m/z found 382.0 [M+H]⁺. ¹H NMR (CD₃OD): 8.47(d, J=5.5 Hz, 1H), 8.37 (d, J=8.9 Hz, 1H), 8.06 (dd, J=8.9, 5.5 Hz, 1H),6.83 (s, 1H), 4.36-4.24 (m, 2H), 4.10-3.97 (m, 3H), 3.81-3.67 (m, 4H),3.50-3.44 (m, 1H), 3.39-3.33 (m, 1H), 3.30-3.22 (m, 1H), 2.54 (s, 6H),1.92-1.80 (m, 2H), 1.03 (t, J=7.4 Hz, 3H).

The following prophetic example may be prepared using the proceduresdescribed in the previous examples.

Example 345:(3-Propoxypyridin-2-yl)(5-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

MS (ESI) mass calcd. For C₂₀H₂₃F₃N₅O₂, 421.17.

Example 346:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-fluoro-2-(3-fluoropyridin-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 248,substituting 3-fluoro-2-(tributylstannyl)pyridine for5-methyl-2-(tributylstannyl)pyridine. MS (ESI) mass calcd. forC₂₄H₂₃F₂N₅O, 435.19; found 436.2 [M+H]⁺.

Prophetic examples 347-348 may be prepared using the proceduresdescribed in the previous examples.

Example 347:(3-Propoxypyridin-2-yl)(5-(quinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

MS (ESI) mass calcd. For C₂₃H₂₅N₅O₂, 403.20.

Example 348:2-(5-([1,1′-biphenyl]-2-ylsulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)quinoxaline

The title prophetic compound may be synthesized usingbiphenylsulfonylchloride and Intermediate 35. MS (ESI) mass calcd. forC₂₆H₂₄N₄O₂S, 456.16.

Example 349:2-[(2,6-Dimethoxyphenyl)carbonyl]-5-[5-(trifluoromethyl)pyridin-2-yl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15,utilizing 5-(trifluoromethyl)pyridin-2-yl]octahydropyrrolo[3,4-c]pyrroleand 2,6-dimethoxybenzoic acid. MS (ESI) mass calcd. C₂₁H₂₂F₃N₃O₃,421.42. m/z found 422.0 [M+H]⁺. ¹H NMR (CD₃OD): 8.23 (s, 1H), 8.12 (d,J=8.9 Hz, 1H), 7.34 (t, J=8.4 Hz, 1H), 7.27 (d, J=9.2 Hz, 1H), 6.72-6.66(m, 2H), 4.03-3.48 (m, 14H), 3.28-3.22 (m, 2H).

Example 350:(2,6-Dimethoxyphenyl)(5-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title prophetic compound may be synthesized in a manner analogous toExample 15 utilizing5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole and2,6-dimethoxybenzoic acid. MS (ESI) mass calcd. For C₂₀H₂₁F₃N₄O₃,422.16.

Example 351:(2,6-Dimethoxyphenyl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner analogous to Example 15utilizing in a manner analogous to Example 15, utilizing Intermediate 23and 2,6-dimethoxybenzoic acid. MS (ESI) mass calcd. C₂₁H₂₆N₄O₃, 382.47.m/z found 383.1 [M+H]⁺. ¹H NMR (CD₃OD): 7.38 (t, J=8.4 Hz, 1H), 6.81 (s,1H), 6.81-6.70 (m, 2H), 4.04-3.89 (m, 3H), 3.84 (s, 3H), 3.79 (s, 3H),3.76-3.55 (m, 4H), 3.27-3.13 (m, 3H), 2.53 (s, 6H).

Example 352:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-methylfuran-2-yl)methanone

The title compound was prepared in a manner analogous to Example 15,substituting 3-methylfuran-2-carboxylic acid for3-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid. MS (ESI) mass calcd. ForC₁₈H₂₂N₄O₂, 326.17. m/z found 327.2 [M+H]⁺.

Example 353:2-[(3-Methylfuran-2-yl)carbonyl]-5-[5-(trifluoromethyl)pyridin-2-yl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15,utilizing2-(5-(trifluoromethyl)pyridin-2-yl)octahydropyrrolo[3,4-c]pyrrole and3-methylfuran-2-carboxylic acid. MS (ESI) mass calcd. C₁₈H₁₈F₃N₃O₂,365.36. m/z found 366.0 [M+H]⁺. ¹H NMR (CDCl₃): 8.39 (s, 1H), 7.62 (d,J=9.1 Hz, 1H), 7.32 (d, J=1.4 Hz, 1H), 6.39 (d, J=8.8 Hz, 1H), 6.32 (d,J=1.4 Hz, 1H), 4.17 (brs, 1H), 3.94 (brs, 1H), 3.81 (brs, 3H), 3.71-3.67(m, 1H), 3.50 (br s, 2H), 3.11 (brs, 2H), 2.37 (s, 3H).

Example 354:(3-Methylfuran-2-yl)(5-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title prophetic compound may be prepared analogous to Example 15,utilizing5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole and3-methylfuran-2-carboxylic acid. MS (ESI) mass calcd. For C₁₇H₁₇F₃N₄O₂,366.13.

Example 355:(3-Methylfuran-2-yl)(5-(quinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-ylmethanone

The title compound was prepared in a manner analogous to Example 15utilizing Intermediate 35 and 3-methylfuran-2-carboxylic acid. MS (ESI)mass calcd. For C₂₀H₂₀N₄O₂, 348.16. m/z found 349.0 [M+H]⁺.

Example 356:2-([1,1′-Biphenyl]-2-ylsulfonyl)-5-(5-(trifluoromethyl)pyridin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound may be prepared using biphenylsulfonylchloride and5-(trifluoromethyl)pyridin-2-yl)octahydropyrrolo[3,4-c]pyrrole. MS (ESI)mass calcd. For C₂₄H₂₂F₃N₃O₂S, 473.14. m/z found 474.1 [M+H]⁺.

Example 357:2-([1,1′-Biphenyl]-2-ylsulfonyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title prophetic compound may be prepared usingbiphenylsulfonylchloride and5-(trifluoromethyl)pyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole MS(ESI) mass calcd. For C₂₃H₂₁F₃N₄O₂S, 474.13.

Example 358:2-([1,1′-Biphenyl]-2-ylsulfonyl)-5-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared using biphenylsulfonylchloride and4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole. MS (ESI) masscalcd. For C₂₄H₂₆N₄O₂S, 434.18. m/z found 435.2 [M+H]⁺.

Example 359:2-(4,6-Dimethylpyrimidin-2-yl)-5-((2-methoxyphenyl)sulfonyl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared using 2-methoxyphenyl)sulfonylchlorideand Intermediate 23. MS (ESI) mass calcd. For C₁₉H₂₄N₄O₃S, 388.16. m/zfound 389.2 [M+H]⁺.

Example 360:2-((2-Methoxyphenyl)sulfonyl)-5-(5-(trifluoromethyl)pyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title prophetic compound may be prepared using2-methoxyphenyl)sulfonylchloride and5-(trifluoromethyl)pyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole. MS(ESI) mass calcd. For C₁₈H₁₉F₃N₄O₃S, 428.11.

Example 361:2-((2-Methoxyphenyl)sulfonyl)-5-(5-(trifluoromethyl)pyridin-2-yl)octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared using 2-methoxyphenyl)sulfonylchlorideand 5-(trifluoromethyl)pyridin-2-yl)octahydropyrrolo[3,4-c]pyrrole. MS(ESI) mass calcd. For C₁₉H₂₀F₃N₃O₃S, 427.12. m/z found 428.2 [M+H]⁺.

Example 362:2-(5-((2-Methoxyphenyl)sulfonyl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)quinoxaline

The title compound was prepared using 2-methoxyphenyl)sulfonylchlorideand Intermediate 35. MS (ESI) mass calcd. For C₂₁H₂₂N₄O₃S, 410.14. m/zfound 411.1 [M+H]⁺.

Prophetic Examples 363-365 may be prepared as previously described.

Example 363:(3,6′-Dimethyl-[2,3′-bipyridin]-2′-yl)(5-(quinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

MS (ESI) mass calcd. For C₂₇H₂₆N₆O, 450.22.

Example 364:(3,6′-Dimethyl-[2,3′-bipyridin]-2′-yl)(5-(5-(trifluoromethyl)pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

MS (ESI) mass calcd. For C₂₇H₂₃F₃N₆O, 468.19.

Example 365:(3,6′-Dimethyl-[2,3′-bipyridin]-2′-yl)(5-(5-(trifluoromethyl)pyridin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

MS (ESI) mass calcd. For C₂₅H₂₄F₃N₅O, 467.19.

Example 366:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-fluoro-2-(pyridin-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 367substituting(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-fluoro-2-iodophenyl)methanonefor(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-iodophenyl)methanone,with the addition of catalytic CuI, substituting dioxane for DME,heating 130° C. in microwave for 60 min. The reaction was filteredthrough celite, rinsed with EtOAc and then concentrated and purified onRP agilent HPLC and fractions lyophilized. MS (ESI) mass calcd. forC₂₄H₂₄FN₅O, 417.20. m/z found, 418.2 [M+H]⁺.

Example 367:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-(pyridin-2-yl)phenyl)methanone

(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-(pyridin-2-yl)phenyl)methanone.(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-iodophenyl)methanone(51 mg, 0.11 mmol) and 2-tributylstannane pyridine (57 mg, 0.13 mmol)were combined and dissolved in degassed DME then purged with bubbling N₂for 5 minutes. The reaction was treated with Pd(PPh₃)₄ and then purgedwith bubbling for 5 minutes in a sealed vessel and then heated to 160°C. in microwave for 90 min. Reaction was filtered through celite,concentrated and purified on 16 g SiO₂ with 0-3.5% NH₃ MeOH/CH₂Cl₂. MS(ESI) mass calcd. for C₂₄H₂₄FN₅O, 417.49. m/z found, 418.2 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): 7.71-7.64 (m, 1H), 7.57-7.52 (m, 1H), 7.46 (dddd,J=8.2, 5.6, 2.8, 1.2 Hz, 1H), 7.37 (td, J=7.9, 5.5 Hz, 1H), 7.30-7.24(m, 2H), 7.20 (ddd, J=9.0, 2.5, 1.5 Hz, 1H), 7.11 (tdd, J=8.4, 2.6, 1.0Hz, 1H), 6.31 (s, 1H), 3.97 (dd, J=12.7, 7.8 Hz, 1H), 3.89 (dd, J=11.5,7.7 Hz, 1H), 3.82-3.70 (m, 2H), 3.70-3.60 (m, 2H), 3.50 (dd, J=11.5, 4.6Hz, 1H), 3.40 (dd, J=10.9, 5.4 Hz, 1H), 3.07 (d, J=7.2 Hz, 1H),3.03-2.94 (m, 1H), 2.30 (s, 6H).

Example 368:[2,3′-bipyridin]-2′-yl(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title prophetic example may be synthesized according to a procedureas previously described. MS (ESI) mass calcd. for C₂₃H₂₄N₆O, 400.48

Example 369:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-fluoro-2-(oxazol-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 248,substituting 2-(tri-N-butylstannyl)oxazole for 2-tributylstannanepyrimidine. MS (ESI) mass calcd. for C₂₂H₂₂FN₅O₂, 407.18; found 408.2[M+H]⁺.

Example 370:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-(6-methylpyridin-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 367,substituting 6-methyl-2-(tributylstannyl)pyridine for 2-tributylstannanepyridine. MS (ESI) mass calcd. for C₂₅H₂₆FN₅O, 431.51. m/z found, 432.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.60 (t, J=7.7 Hz, 1H), 7.43-7.35 (m,2H), 7.21-7.15 (m, J=13.8, 4.5 Hz, 2H), 7.05 (d, J=7.7 Hz, 1H), 6.30 (s,1H), 3.84-3.73 (m, J=20.1, 12.0, 7.6 Hz, 2H), 3.67 (dd, J=11.5, 7.0 Hz,1H), 3.63-3.53 (m, 1H), 3.40 (t, J=13.3 Hz, 2H), 3.30-3.20 (m, 1H), 3.10(dd, J=10.8, 5.7 Hz, 1H), 2.98-2.84 (m, 2H), 2.43 (s, 3H), 2.30 (s, 6H).

Example 371:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-(3-methylpyridin-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 367. MS(ESI) mass calcd. for C₂₅H₂₆FN₅O, 431.51. m/z found, 432.2 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃): 8.37 (d, J=40.0 Hz, 1H), 7.56-7.49 (m, 1H), 7.41(td, J=7.9, 5.3 Hz, 1H), 7.23-7.04 (m, J=19.5, 9.7 Hz, 3H), 6.30 (s,1H), 3.96-3.45 (m, 6H), 3.46-3.19 (m, J=11.6, 7.6 Hz, 2H), 3.01-2.85 (m,2H), 2.31 (s, 6H), 2.23 (s, 3H).

Example 372:(2-(3-Chloropyridin-2-yl)-3-fluorophenyl)(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title compound was prepared in a manner analogous to Example 367. MS(ESI) mass calcd. for C₂₄H₂₃ClFN₅O, 451.93. m/z found, 452.1 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): 8.51 (d, J=3.7 Hz, 1H), 7.71 (dd, J=28.1, 8.0 Hz,1H), 7.45 (td, J=7.9, 5.3 Hz, 1H), 7.25-7.14 (m, J=10.6, 7.7 Hz, 3H),6.30 (s, 1H), 3.77 (s, 2H), 3.72-3.59 (m, J=23.3, 9.8 Hz, 2H), 3.59-3.53(m, 1H), 3.45 (dd, J=33.2, 12.0 Hz, 2H), 3.37-3.11 (m, J=59.6 Hz, 1H),3.02-2.88 (m, 2H), 2.31 (s, 6H).

Example 373:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-(4-methylpyridin-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 367. MS(ESI) mass calcd. for C₂₅H₂₆FN₅O, 431.51. m/z found, 432.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): 8.44 (d, J=5.0 Hz, 1H), 7.43-7.40 (m, 1H),7.40-7.34 (m, 1H), 7.21-7.14 (m, J=2.7, 1.1 Hz, 2H), 6.99 (d, J=4.5 Hz,1H), 6.29 (s, 1H), 3.79 (dd, J=11.5, 7.3 Hz, 1H), 3.69 (ddd, J=8.7, 7.1,2.1 Hz, 2H), 3.58-3.50 (m, 2H), 3.46 (dd, J=12.6, 4.3 Hz, 1H), 3.40 (dd,J=10.9, 4.2 Hz, 1H), 3.25 (dd, J=11.0, 5.1 Hz, 1H), 2.99-2.85 (m, 2H),2.34 (s, 3H), 2.31 (s, 6H).

Example 374:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-(5-methylpyridin-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 367. MS(ESI) mass calcd. for C₂₅H₂₆FN₅O, 431.51. m/z found, 432.2 [M+H]⁺. ¹HNMR (400 MHz, CDCl₃): 8.42 (s, 1H), 7.53-7.48 (m, 2H), 7.42-7.33 (m,1H), 7.21-7.12 (m, 2H), 6.29 (s, 1H), 3.81 (dd, J=11.5, 7.3 Hz, 1H),3.76-3.67 (m, J=11.3, 7.2, 4.3 Hz, 2H), 3.58-3.39 (m, 4H), 3.28 (dd,J=10.9, 4.8 Hz, 1H), 3.01-2.86 (m, 2H), 2.31 (s, 9H).

Example 375:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-(3-fluoropyridin-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 367substituting 3-fluoro-2-(tributylstannyl)pyridine for 2-tributylstannanepyridine. MS (ESI) mass calcd. for C₂₄H₂₃F₂N₅O, 435.48. m/z found, 436.2[M+H]⁺. ¹H NMR (400 MHz, CDCl₃): 8.45 (dt, J=4.6, 1.5 Hz, 1H), 7.49-7.39(m, 2H), 7.29-7.16 (m, 3H), 6.30 (s, 1H), 3.85-3.60 (m, 5H), 3.53-3.42(m, 2H), 3.38 (dd, J=10.9, 4.4 Hz, 1H), 3.03-2.91 (m, 2H), 2.31 (s, 6H).

Example 376:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-(oxazol-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 367substituting 2-(tri-N-butylstannyl)oxazole for 2-tributylstannanepyridine. MS (ESI) mass calcd. for C₂₂H₂₂FN₅O₂, 407.45. m/z found, 408.2[M+H]⁺. ¹H NMR (500 MHz, CDCl₃): 7.73 (d, J=0.6 Hz, 1H), 7.51-7.44 (m,1H), 7.25-7.20 (m, 2H), 7.18 (dd, J=7.6, 0.9 Hz, 1H), 6.29 (s, 1H),3.90-3.83 (m, 2H), 3.74-3.60 (m, 3H), 3.52 (dd, J=11.6, 4.4 Hz, 1H),3.45 (dd, J=10.9, 7.5 Hz, 1H), 3.11 (dd, J=10.9, 5.4 Hz, 1H), 3.08-3.00(m, 1H), 3.00-2.93 (m, 1H), 2.30 (s, 6H).

Example 377:2-(5-Fluoro-4-methylpyrimidin-2-yl)-5-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone(Example 288—step B, 33 mg, 0.10 mmol),2-chloro-5-fluoro-4-methylpyrimidine (Intermediate 55, 15 mg, 0.10 mmol)and DIPEA (54 μL, 0.3 mmol) in ACN (1 mL) were heated in a microwavereactor for 2 h at 200° C. Then the reaction mixture was concentratedand purified via prep HPLC (Agilent, basic) gave the title compound as aclear oil. MS (ESI) mass calcd. C₂₁H₂₂FN₇O₂, 423.45. m/z found 424.2[M+H]⁺. ¹H NMR (CDCl₃): 8.06 (d, J=1.8 Hz, 1H), 7.74 (s, 2H), 7.50 (d,J=5.8 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 6.95 (dd, J=8.5, 2.5 Hz, 1H),3.93-3.76 (m, 5H), 3.71-3.59 (m, 2H), 3.53 (dd, J=11.4, 5.2 Hz, 1H),3.44-3.30 (m, 2H), 3.07-2.87 (m, 3H), 2.37 (t, J=4.9 Hz, 3H).

Example 378:2-(5-Chloro-4-methylpyrimidin-2-yl)-5-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 377,utilizing 2,5-dichloro-4-methylpyrimidine (Intermediate 65) in place of2-chloro-5-fluoro-4-methylpyrimidine. MS (ESI) mass calcd. C₂₁H₂₂ClN₇O₂,439.91. m/z found 440.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.13 (s, 1H), 7.74 (s,2H), 7.51 (d, J=10.9 Hz, 1H), 7.32 (d, J=6.8 Hz, 1H), 6.94 (dd, J=20.6,10.3 Hz, 1H), 3.93-3.78 (m, 5H), 3.73-3.60 (m, 2H), 3.59-3.50 (m, 1H),3.47-3.30 (m, 2H), 3.08-2.87 (m, 3H), 2.44 (s, J=11.6 Hz, 3H).

Example 379:2-(5-Fluoro-4,6-dimethylpyrimidin-2-yl)-5-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 377,utilizing 2-chloro-5-fluoro-4,6-dimethylpyrimidine (Intermediate 69) inplace of 2-chloro-5-fluoro-4-methylpyrimidine. MS (ESI) mass calcd.C₂₂H₂₄FN₇O₂, 437.48; m/z found 438.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.74 (s,2H), 7.50 (d, J=2.5 Hz, 1H), 7.35-7.30 (m, 1H), 6.95 (dd, J=8.5, 2.5 Hz,1H), 3.92-3.75 (m, 5H), 3.70-3.58 (m, 2H), 3.53 (dd, J=11.5, 5.2 Hz,1H), 3.43-3.29 (m, 2H), 3.04-2.84 (m, 3H), 2.32 (d, J=6.7 Hz, 6H).

Example 380:2-(4,5-Dimethylpyrimidin-2-yl)-5-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 377,utilizing 2-chloro-4,5-dimethylpyrimidine (Intermediate 57) in place of2-chloro-5-fluoro-4-methylpyrimidine. MS (ESI) mass calcd. C₂₂H₂₅N₇O₂,419.49. m/z found 420.1 [M+H]⁺. ¹H NMR (CDCl₃): 7.99 (s, 1H), 7.74 (s,2H), 7.49 (d, J=7.3 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 6.94 (dd, J=8.5,2.5 Hz, 1H), 3.92-3.78 (m, 5H), 3.72-3.61 (m, 2H), 3.54 (dd, J=11.4, 5.2Hz, 1H), 3.42 (dd, J=11.4, 4.2 Hz, 1H), 3.34 (s, 1H), 3.07-2.85 (m, 3H),2.32 (s, 3H), 2.09 (s, 3H).

Example 381:2-[(3-Propoxypyridin-2-yl)carbonyl]-5-[5-(trifluoromethyl)pyridin-2-yl]octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 15,utilizing 5-(trifluoromethyl)pyridin-2-yl]octahydropyrrolo[3,4-c]pyrroleand 2-propoxynicotinic acid. MS (ESI) mass calcd. C₂₁H₂₃F₃N₄O₂, 420.40.m/z found 421.1 [M+H]⁺. ¹H NMR (CD₃OD): 8.31 (s, 2H), 8.19 (dd, J=9.6,2.3 Hz, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 7.26 (d, J=9.4 Hz, 1H),4.22-4.17 (m, 2H), 4.07-3.93 (m, 3H), 3.79-3.60 (m, 4H), 3.44-3.35 (m,3H), 1.88-1.77 (m, 2H), 1.02 (t, J=7.4 Hz, 3H).

Example 382:2-{4,6-Bis[(²H₃)methyl](²H)pyrimidin-2-yl}-5-{[2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

To a solution of Intermediate 91 (150 mg, 0.26 mmol) in DCM (2.6 mL) wasadded Intermediate 12 (55 mg, 0.26 mmol) followed by EDCl (76 mg, 0.4mmol), HOBt (54 mg, 0.4 mmol) and TEA (0.15 mL, 1.06 mmol). The mixturewas stirred for 14 h at room temperature and an additional amount ofEDCl (76 mg, 0.4 mmol) and TEA (0.15 mL, 1.06 mmol) were added. After anadditional 24 h at room temperature the mixture was concentrated invacuo and chromatography (Hex to 100% EtOAc/Hex) afforded the desiredproduct as a colorless foam (63 mg, 58%). MS (ESI): mass calculated forC₂₁H₁₅D₇FN₇O, 414.23. m/z found 415.2 [M+1]⁺. 1 H NMR (500 MHz, CDCl₃):7.87-7.80 (m, 2H), 7.71 (s, 1H), 7.51-7.44 (m, 1H), 7.18-7.10 (m, 1H),4.01-3.50 (m, 7H), 3.32-3.21 (m, 1H), 3.12-2.94 (m, 2H).

Example 383:2-{4,6-Bis[(²H₃)methyl](²H)pyrimidin-2-yl}-5-{[3-fluoro-2-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 382substituting Intermediate 63 for Intermediate 12. MS (ESI): masscalculated for C₂₂H₁₆D₇FN₆O₂, 429.23. m/z found 430.2 [M+1]⁺. 1 H NMR(500 MHz, CDCl₃): 7.63-7.57 (m, 1H), 7.31-7.27 (m, 1H), 7.24-7.21 (m,1H), 3.94-3.87 (m, 2H), 3.78-3.62 (m, 3H), 3.58-3.48 (m, 2H), 3.22-3.15(m, 1H), 3.12-2.96 (m, 2H), 2.43 (s, 3H).

Example 384:2-{4,6-Bis[(²H₃)methyl](²H)pyrimidin-2-yl}-5-{[4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 382substituting Intermediate 54 for Intermediate 12. MS (ESI): masscalculated for C₂₂H₁₈D₇N₇O₂, 426.25. m/z found 427.3 [M+1]⁺. ¹H NMR (500MHz, CDCl₃): 7.73 (s, 2H), 7.50 (d, J=2.5 Hz, 1H), 7.33 (d, J=8.5 Hz,1H), 6.95 (dd, J=8.5 Hz, 2.5 Hz, 1H), 3.94-3.80 (m, 5H), 3.71-3.63 (m,2H), 3.61-3.55 (m, 1H), 3.49-3.43 (m, 1H), 3.38-3.29 (m, 1H), 3.05-2.86(m, 3H).

Example 385:2-(5-Ethyl-4,6-dimethylpyrimidin-2-yl)-5-{[3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

The title compound was prepared in a manner analogous to Example 290substituting Intermediate 68 for Intermediate 20 and Intermediate 67 forIntermediate 55. MS (ESI) mass calculated for C₂₂H₂₆N₅O, 418.22. m/zfound, 419.2. 1H NMR (500 MHz, CDCl₃): 8.62 (dd, J=4.7 Hz, 1.3 Hz, 1H),8.33 (dd, J=8.3 Hz, 1.4 Hz, 1H), 7.79 (s, 2H), 7.48 (dd, J=8.3 Hz, 4.7Hz, 1H), 3.97-3.84 (m, 2H), 3.78-3.63 (m, 4H), 3.59-3.55 (m, 1H),3.29-3.23 (m, 1H), 3.13-2.98 (m, 2H), 2.52 (q, J=7.5 Hz, 2H), 2.38 (s,6H), 1.08 (t, J=7.5 Hz, 3H).

Example 386:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole

Step A: 2-(Methoxycarbonyl)nicotinic acid. 2,3-Pyridinecarboxylicanhydride (2.32 g, 15.55 mmol) was dissolved in MeOH (11 mL) and heatedto reflux for 14 h. The mixture was concentrated in vacuo to a whitesolid that was a mixture of 2-(methoxycarbonyl)nicotinic acid and3-(methoxycarbonyl)picolinic acid. This mixture was used as is. MS (ESI)mass calculated for C₈H₇NO₄, 181.04. m/z found, 181.9.

Step B: (E)-Methyl 3-((((1-aminoethylidene)amino)oxy)carbonyl)picolinate. To the product of Step A (250 mg, 1.38 mmol) in THE (7 mL)at 0° C. was added ethyl chloroformate (0.17 mL, 1.38 mmol) followed byTEA (0.29 mL, 2.07 mmol). After 10 min the ice bath was removed andafter 2 h N-hydroxyacetamidine (102 mg, 1.38 mmol) was added in oneportion. After 14 h at room temperature the mixture was concentrated invacuo and chromatography (Hex to 100% EtOAc/Hex) afforded the desired(E)-methyl 3-((((1-aminoethylidene)amino)oxy)carbonyl)picolinate (200mg, 70%) and (E)-methyl2-((((1-aminoethylidene)amino)oxy)carbonyl)nicotinate (60 mg, 18%). MS(ESI) mass calculated for C₁₀H₁₁N₃O₄, 237.08. m/z found, 238.1. 1H NMR(500 MHz, CDCl₃): 8.79 (dd, J=4.8 Hz, 1.6 Hz, 1H), 8.28 (dd, J=7.9 Hz,1.6 Hz, 1H), 7.58-7.51 (m, 1H), 3.99 (s, 3H), 2.04 (s, 3H).

Step C: 3-(3-Methyl-1,2,4-oxadiazol-5-yl)picolinic acid. To the productof Step B (180 mg, 0.76 mmol) was added t-BuOH (4 mL) followed by NaOAc(94 mg, 1.14 mmol) and the mixture was heated at 100° C. for 14 h. Themixture was allowed to cool to room temperature and filtered to afford3-(3-methyl-1,2,4-oxadiazol-5-yl)picolinic acid (60 mg, 39%) as a whitesolid.

Step D:2-(4,6-Dimethylpyrimidin-2-yl)-5-{[3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl]carbonyl}octahydropyrrolo[3,4-c]pyrrole.To a solution of the product of Step C (60 mg, 0.30 mmol) in DCM (3 mL)was added Intermediate 23 (65 mg, 0.30 mmol) followed by EDCl (85 mg,0.44 mmol), HOBt (60 mg, 0.44 mmol) and TEA (0.08 mL, 0.59 mmol). Themixture was stirred at room temperature for 14 h and then concentratedin vacuo. Chromatography (DCM to 8% 2 M NH₃ in MeOH/DCM) afforded thedesired compound as a colorless foam (49 mg, 41%). MS (ESI) masscalculated for C₂₁H₂₃N₇O₂, 405.19. m/z found, 406.2. 1H NMR (500 MHz,CDCl₃): 8.82-8.75 (m, 1H), 8.42-8.36 (m, 1H), 7.52-7.47 (m, 1H),6.31-6.26 (m, 1H), 4.02-3.90 (m, 2H), 3.86-3.79 (m, 1H), 3.76-3.69 (m,2H), 3.66-3.54 (m, 2H), 3.24-3.18 (m, 1H), 3.14-2.99 (m, 2H), 2.48-2.42(m, 3H), 2.33-2.24 (m, 6H).

Example 387:(5-(6,7-Difluoroquinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 44 and Intermediate 50 in the last step MS (ESI):mass calculated for C₂₅H₁₉F₃N₆O, 476.16. m/z found 477.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃) 8.74 (t, J=12.5, 2H), 8.25 (d, J=20.5, 1H), 7.65 (dd,J=10.5, 8.4, 1H), 7.52-7.40 (m, 2H), 7.26-7.12 (m, 3H), 3.97-3.74 (m,3H), 3.73-3.52 (m, 4H), 3.38 (dd, J=11.1, 4.6, 1H), 3.22-3.02 (m, 2H).

Example 388:(5-(6,7-Difluoroquinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 43 and Intermediate 54 in the last step MS (ESI):mass calculated for C₂₄H₂₂FN₇O₂, 459.18. m/z found 460.2 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃) 8.97 (s, 1H), 7.71 (s, 2H), 7.59 (dd, J=9.0, 4.7, 1H),7.47 (ddd, J=17.7, 9.5, 2.6, 2H), 7.37-7.28 (m, 2H), 6.95 (dd, J=8.5,2.5, 1H), 4.01-3.85 (m, 5H), 3.74 (ddt, J=17.0, 11.6, 8.8, 3H),3.64-3.33 (m, 2H), 3.12-2.93 (m, 3H).

Example 389:(5-(6,7-Difluoroquinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 15,utilizing Intermediate 44 and Intermediate 54 in the last step MS (ESI):mass calculated for C₂₄H₂₁F₂N₇O₂, 477.17. m/z found 478.1 [M+H]⁺. ¹H NMR(500 MHz, CDCl₃) 8.26 (d, J=14.7, 1H), 7.71 (s, 2H), 7.63 (dd, J=10.6,8.5, 1H), 7.49 (t, J=7.1, 1H), 7.41 (dd, J=11.4, 8.0, 1H), 7.33 (t,J=6.7, 1H), 6.95 (dt, J=8.4, 4.2, 1H), 3.99-3.85 (m, 5H), 3.83-3.69 (m,2H), 3.70-3.57 (m, 1H), 3.52 (dd, J=11.0, 3.5, 1H), 3.44 (s, 1H),3.19-3.09 (m, 1H), 3.09-2.97 (m, 2H).

Example 390:(5-(6-(Dimethylamino)pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

The title compound was prepared utilizing(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone(Example 288, product from Step B) and6-chloro-N,N-dimethylpyrimidin-4-amine. MS (ESI) mass calcd. C₂₂H₂₆NO₂,434.49. m/z found 435.2 [M+H]⁺.

Example 391:(5-(6-(Dimethylamino)-2-methylpyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone

The title compound was prepared utilizing(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone(Example 288, product from Step B) and6-chloro-N,N,2-trimethylpyrimidin-4-amine. MS (ESI) mass calcd.C₂₃H₂₆N₈O₂, 448.52. m/z found 449.2 [M+H]⁺.

Prophetic examples 392-398 may be made using the procedures describedpreviously.

Example 392:(5-(6-(Dimethylamino)-2-methylpyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone

The title prophetic compound may be synthesized utilizing6-chloro-N,N,2-trimethylpyrimidin-4-amine and MS (ESI) mass calcd.C₂₄H₂₆FN₇O, 447.51

Example 393:(5-(6-(Dimethylamino)pyrimidin-4-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone

The title prophetic compound may be synthesized utilizing3-fluoro-2-(pyrimidin-2-yl)benzoic acid and6-chloro-N,N-dimethylpyrimidin-4-amine. MS (ESI) mass calcd. C₂₃H₂₄FN₇O,433.48

Example 394:(3-Fluoro-2-(pyrimidin-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title prophetic compound may be synthesized utilizing3-fluoro-2-(pyrimidin-2-yl)benzoic acid and2-chloro-5-fluoro-4,6-dimethylpyrimidine. MS (ESI) mass calcd.C₂₃H₂₂F₂N₆O, 436.46

Example 395:(5-(5-Chloro-4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone

The title prophetic compound may be synthesized utilizing3-fluoro-2-(pyrimidin-2-yl)benzoic acid and2,5-dichloro-4,6-dimethylpyrimidine. MS (ESI) mass calcd. C₂₃H₂₂ClFN₆O₂,452.91

Example 396:(5-(5-Chloro-4-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone

The title prophetic compound may be synthesized utilizing3-fluoro-2-(pyrimidin-2-yl)benzoic acid and2,5-dichloro-4-methylpyrimidine. MS (ESI) mass calcd. C₂₂H₂₀ClFN₆O,438.89.

Example 397:(3-Fluoro-2-(pyrimidin-2-yl)phenyl)(5-(5-fluoro-4-methylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

The title prophetic compound may be synthesized utilizing3-fluoro-2-(pyrimidin-2-yl)benzoic acid and2-chloro-5-fluoro-4-methylpyrimidine. MS (ESI) mass calcd. C₂₂H₂₀F₂N₆O,434.49.

Example 398:(5-(4,5-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-fluoro-2-(pyrimidin-2-yl)phenyl)methanone

MS (ESI) mass calcd. C₂₃H₂₃FN₆O, 418.47

Example 399:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-fluoro-2-(6-methylpyridin-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 248,substituting(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-fluoro-2-iodophenyl)methanonefor(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(4-fluoro-2-iodophenyl)methanoneand 6-methyl-2-(tributylstannyl)pyridine for 2-tributylstannanepyrimidine, with the addition of CuI. MS (ESI) mass calcd. forC₂₅H₂₆FN₅O, 431.21. m/z found 432.2 [M+1]⁺.

Example 400:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-fluoro-2-(4-methylpyridin-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 399,substituting 4-methyl-2-(tributylstannyl)pyridine for6-methyl-2-(tributylstannyl)pyridine. MS (ESI) mass calcd. forC₂₅H₂₆FN₅O, 431.21. m/z found 432.2 [M+1]⁺.

Example 401:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-fluoro-2-(5-methylpyridin-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 399,substituting 5-methyl-2-(tributylstannyl)pyridine for6-methyl-2-(tributylstannyl)pyridine. MS (ESI) mass calcd. forC₂₅H₂₆FN₅O, 431.21. m/z found 432.2 [M+1]⁺.

Example 402:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-fluoro-2-(3-fluoropyridin-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 399,substituting 3-fluoro-2-(tributylstannyl)pyridine for6-methyl-2-(tributylstannyl)pyridine. MS (ESI) mass calcd. forC₂₄H₂₃F₂N₅O, 435.19. m/z found 436.2 [M+1]⁺.

Example 403:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-fluoro-2-(pyridin-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 399,substituting 2-tri-N-butylstannylpyridine for6-methyl-2-(tributylstannyl)pyridine. MS (ESI) mass calcd. forC₂₄H₂₄FN₅O, 417.20. m/z found 418.2 [M+1]⁺.

Example 404:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(5-fluoro-2-(oxazol-2-yl)phenyl)methanone

The title compound was prepared in a manner analogous to Example 399,substituting 2-(tri-N-butylstannyl)oxazole for6-methyl-2-(tributylstannyl)pyridine. MS (ESI) mass calcd. forC₂₂H₂₂FN₅O₂, 407.18; ¹H NMR (400 MHz, CDCl₃): 8.04 (dd, J=8.8, 5.3 Hz,1H), 7.65 (s, 1H), 7.20-7.13 (m, 2H), 7.07 (dd, J=8.3, 2.6 Hz, 1H), 6.29(s, 1H), 3.95 (dd, J=12.6, 7.6 Hz, 1H), 3.88 (dd, J=11.6, 7.6 Hz, 1H),3.78-3.63 (m, 3H), 3.51-3.45 (m, 1H), 3.41 (dd, J=10.8, 7.5 Hz, 1H),3.11-3.02 (m, 2H), 3.00-2.90 (m, 1H), 2.29 (s, 6H).

Prophetic examples 405-410 may be made using the procedures describedpreviously.

Example 405:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-fluoro-2-(6-methylpyridin-2-yl)phenyl)methanone

MS (ESI) mass calcd. for C₂₅H₂₆FN₅O, 431.21;

Example 406:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-fluoro-2-(4-methylpyridin-2-yl)phenyl)methanone

MS (ESI) mass calcd. for C₂₅H₂₆FN₅O, 431.21;

Example 407:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-fluoro-2-(5-methylpyridin-2-yl)phenyl)methanone

MS (ESI) mass calcd. for C₂₅H₂₆FN₅O, 431.21;

Example 408:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-fluoro-2-(3-fluoropyridin-2-yl)phenyl)methanone

MS (ESI) mass calcd. for C₂₄H₂₃F₂N₅O, 435.19;

Example 409:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-fluoro-2-(pyridin-2-yl)phenyl)methanone

MS (ESI) mass calcd. for C₂₄H₂₄FN₅O, 417.20;

Example 410:(5-(4,6-Dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-fluoro-2-(oxazol-2-yl)phenyl)methanone

MS (ESI) mass calcd. for C₂₂H₂₂FN₅O₂, 407.18;

Example 411:(3,6′-Dimethyl-[2,3′-bipyridin]-2′-yl)(5-(quinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

MS (ESI) mass calcd. For C₂₇H₂₆N₆O, 450.22.

Example 412:[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone·HCl·1.65H₂O

To a mixture of[5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone(200 mg, 0.47 mmol) and IPA (1.5 mL) at room temperature was added 6 MHCl_((aq)) (83 μL, 0.5 mmol). The mixture was warmed to 75° C. and thenslowly cooled to 35° C. The mixture was then seeded with solids formedpreviously [The seeds were formed as follows: To a mixture of[5-(4,6-dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone(200 mg, 0.47 mmol) and IPA (2 mL) at room temperature was added 5 M HClin IPA (100 μL, 0.5 mmol). The mixture became homogeneous and wasstirred at room temperature for 3 weeks. Solids formed when the solventwas allowed to evaporate under an ambient atmosphere.]. Once seeded, themixture was cooled to room temperature and stirred for 3 days. Theresulting solids were filtered and washed with IPA (0.5 mL). The solidswere then dried in a vacuum oven for 2 h at 45° C. to give the titlecompound as a white solid (201.9 mg, 91%). ¹H NMR (600 MHz, DMSO-d₆):8.16 (s, 0.8H), 8.05 (s, 1.2H), 7.83 (d, J=8.2, 0.4H), 7.79 (d, J=8.2,0.6H), 7.70-7.64 (m, 1H), 7.48-7.41 (m, 1H), 6.71 (bs, 1H), 4.0-3.4 (m,7H), 3.25-2.96 (m, 3H), 2.48-2.33 (m, 6H). Anal. Calcd. ForC₂₁H₂₂FN₇O·HCl·1.65H₂O C, 53.25; H, 5.60; N, 20.70; Cl, 7.49. found C,53.54; H, 5.64; N, 21.04; Cl, 7.10. Water calculated, 6.28%. found byKarl-Fisher titration, 6.32%.

Biological Assays

The in vitro affinity of the compounds for the human orexin-1 andorexin-2 receptors was determined by competitive radioligand bindingusing [³H]SB SB674042(1-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-1-((S)-2-(5-phenyl-(1,3,4)oxadiazol-2-ylmethyl)-pyrrolidin-1-yl)-methanone)(Langmead et al., British Journal of Pharmacology 2004, 141:340-346.)and [³H]EMPA(N-ethyl-2[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethylacetamide) (Malherbe et al., British Journal of Pharmacology, 2009,156(8), 1326-1341), respectively.

The in vitro functional antagonism of the compounds on the humanorexin-1 and orexin-2 receptors was determined using fluorometricimaging plate reader (FLIPR) based calcium assays.

Human Orexin 1 Receptor Radioligand Binding Studies

Chinese ovary cells (CHO) stably expressing human orexin 1 receptor(Genebank accession number NM_001526) were grown to confluency inDMEM/F12 (Gibco, Cat #11039), 10% FBS, 1× Pen/Strep, 600 μg/mL G418media on 150 cm² tissue culture plates, washed with 5 mM EDTA in PBS(HyClone Dulbecco's Phosphate Buffered Saline 1× with Calcium andMagnesium, Cat #SH30264.01, hereafter referred to simply as PBS) andscraped into 50 ml tubes. After centrifugation (2K×G, 10 min at 4° C.),the supernatant was aspirated and the pellets frozen and stored at −80°C. Cells were resuspended in PBS in the presence of 1 tablet of proteaseinhibitor cocktail (Roche, Cat. #11836145001) per 50 mL. Each cellpellet from a 15 cm plate was resuspended in 10 mL, stored on ice, andvortexed for 45 sec prior to addition to the reactions. Competitionbinding experiments in 96 well polypropylene plates were performed using[³H]-SB674042 (Moravek Corporation, specific activity=35.3 Ci/mmol),diluted to a 10 nM concentration in PBS (4 nM final). Compounds weresolubilized in 100% DMSO (Acros Organics, Cat. #61042-1000) and testedover a range of 7 concentrations (from 0.1 nM to 10 μM). The finalconcentration of DMSO in the reactions is equal to or less than 0.1%.Total and nonspecific binding was determined in the absence and presenceof 10 μM(1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)phenyl]urea,CAS Registry #288150-92-5). The total volume of each reaction is 200 μL(20 μL of diluted compounds, 80 μL of [³H]-SB674042 diluted in PBS and100 μL of the cell suspension). Reactions were run for 60 min at roomtemperature and terminated by filtration through GF/C filter plates(PerkinElmer, Cat. #6005174) presoaked in 0.3% polyethylenimine usingthe cell harvester (PerkinElmer Filtermate). The plates were washed 3times by aspirating 30 ml PBS through the plates. Plates were dried in55° C. oven for 60 min, scintillation fluid was added, and theradioactivity was counted on a Topcount (Packard).

IC₅₀ values (i.e. concentration of unlabelled compound required tocompete for 50% of specific binding to the radioligand) were calculatedusing the GraphPad Prism software (GraphPad Prism Software Inc., SanDiego, Calif.) with a fit to a sigmoidal dose-response curve. ApparentK_(i) values were calculated as K_(i)=IC₅₀/(1+C/K_(d)), where C isconcentration of radioligand and K_(d)=4 nM.

Human Orexin 2 Receptor Radioligand Binding Studies

HEK293 stably expressing human orexin-2 receptor (Genebank accessionnumber NM_001526) were grown to confluency in DMEM/F12 (Gibco, Cat#11039), in DMEM, 10% FBS, 1× Pen/Strep, 1× NaPyruvate, 1×HEPES, 600ug/ml G418 media on 150 cm² tissue culture plates, washed with 5 mM EDTAin PBS (HyClone Dulbecco's Phosphate Buffered Saline 1× with Calcium andMagnesium, Cat #SH30264.01, hereafter referred to simply as PBS) andscraped into 50 ml tubes. After centrifugation (2K×G, 10 min at 4° C.),the supernatant was aspirated and the pellets frozen and stored at −80°C. Cells were resuspended in PBS in the presence of 1 tablet of proteaseinhibitor cocktail (Roche, Cat. #11836145001) per 50 mL. Each cellpellet from a 15 cm plate was resuspended in 10 mL, stored on ice, andvortexed for 45 sec just prior to addition to the reactions. Competitionbinding experiments in 96 well polypropylene plates were performed using[³H]-EMPA (Moravek Corporation, specific activity=27 Ci/mmol), dilutedto a 20 nM concentration in PBS (5 nM final concentration). Compoundswere solubilized in 100% DMSO (Acros Organics, Cat. #61042-1000) andtested over a range of 7 concentrations (from 0.1 nM to 10 μM). Thefinal concentration of DMSO in the reactions is equal to or less than0.1%. Total and nonspecific binding was determined in the absence andpresence of 10 μM(N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylnaphthalene-1-carboxamide, CASRegistry #1089563-88-1). The total volume of each reaction is 200 μL (20μL of diluted compounds, 80 μL of [³H]-EMPA diluted in PBS and 100 μL ofthe cell suspension). Reactions were run for 60 min at room temperatureand terminated by filtration through GF/C filter plates (PerkinElmer,Cat. #6005174) presoaked in 0.3% polyethylenimine using the cellharvester (PerkinElmer Filtermate). The plates were washed 3 times byaspirating 30 ml PBS through the plates. Plates were dried in 55° C.oven for 60 min, scintillation fluid was added, and the radioactivitywas counted on a Topcount (Packard). IC₅₀ values (i.e. concentration ofunlabelled compound required to compete for 50% of specific binding tothe radioligand) were calculated using the GraphPad Prism software(GraphPad Prism Software Inc., San Diego, Calif.) with a fit to asigmoidal dose-response curve. Apparent K_(i) values were calculated asK_(i)=IC₅₀/(1+C/K_(d)), where C is concentration of radioligand andK_(d)=2 nM.

Human Orexin 1 Receptor Ca²⁺ Mobilization Assay

CHO cells stably transfected with the human orexin-1 receptor (Genebankaccession number NM_001526) were grown to confluency in DMEM/F12, 10%FBS, 1× Na Pyruvate, 1× pen-strep, 400 μg/ml G418. Cells were seeded onto 96-well Packard viewplates at a density of 50,000 cells/well andincubated overnight at 37° C., 5% CO₂. The cells were dye-loaded with 4μM Ca²⁺ dye Fluo-3AM in serum-free DMEM/F-12 with 2.5 mM probenecid andincubated at 37° C., 5% CO₂ for one hour. Cells were pre-incubated withcompounds (diluted in DMEM/F-12) for 30 minutes before agonist (orexinA, 10 nM) stimulation. Ligand-induced Ca²⁺ release was measured using aFluorometric Imaging Plate Reader (FLIPR, Molecular Devices, Sunnyvale,Calif.). Functional responses were measured as peak fluorescenceintensity minus basal. The concentration of agonist that produced ahalf-maximal response is represented by the EC₅₀ value. Antagonisticpotency values were converted to apparent pK_(B) values using a modifiedCheng-Prusoff correction. Apparent pK_(B)=−log IC₅₀/1+[concagonist/EC₅₀]. Data are expressed as mean±S.E.M.

Human Orexin 2 Receptor Ca²⁺ Mobilization Assay

PFSK cells endogenously expressing the human orexin 2 receptor weregrown to confluency in RPMI1640, 10% FBS, 1× pen-strep. Cells wereseeded on to 96-well Packard viewplates at a density of 50,000cells/well and incubated overnight at 37° C., 5% CO₂. The cells weredye-loaded with 4 μM Ca²⁺ dye Fluo-3AM in serum-free DMEM/F-12 with 2.5mM probenecid and incubated at 37° C., 5% CO₂ for one hour. Cells werepre-incubated with compounds (diluted in DMEM/F-12) for 30 minutesbefore agonist (orexin B, 100 nM) stimulation. Ligand-induced Ca²⁺release was measured using a Fluorometric Imaging Plate Reader (FLIPR,Molecular Devices, Sunnyvale, Calif.). Functional responses weremeasured as peak fluorescence intensity minus basal. The concentrationof agonist that produced a half-maximal response is represented by theEC₅₀ value. Antagonistic potency values were converted to apparentpK_(B) values using a modified Cheng-Prusoff correction. ApparentpK_(B)=−log IC₅₀/1+[conc agonist/EC₅₀]. Data are expressed as meanS.E.M, the designation of NT means not tested.

Ex OR 2 Ki OR 2 OR 1 # (nM) Kb Ki (nM) 1 37 10 100 2 33 16 189 3 42 14127 4 65 32 447 5 14 5 63 6 67 25 154 7 42 13 139 8 542 NT 10000 9 10156 691 10 170 NT 6708 11 1438 NT 10000 12 46 32 4378 13 89 79 10000 1428 9 2780 15 13 2 1824 16 300 NT 10000 17 730 NT NT 18 519 NT 1264 19 2431 77 20 92 129 263 21 352 NT 1091 22 70 158 303 23 364 NT 677 24 415 NT1544 25 110 99 162 26 8999 NT NT 27 740 NT NT 28 575 NT 1787 29 135 NT1009 30 790 NT NT 31 425 NT 651 32 47 32 8999 33 250 NT 488 34 79 NT 14335 722 NT 4370 36 449 NT 1459 37 181 NT 137 38 515 NT 887 39 8999 NT10000 40 559 NT 1433 41 356 NT 2512 42 616 NT 5000 43 7 10 422 44 142 6310000 45 36 10 723 46 132 NT 294 47 38 32 1124 48 716 NT 10000 49 78 321692 50 215 NT 10000 51 644 NT 10000 52 65 50 8999 53 5000 NT 10000 54769 NT 5000 55 744 NT 8999 56 80 40 800 57 167 NT 2323 58 227 NT 5000 59778 NT 8999 60 173 NT 2644 61 224 NT 2272 62 42 40 689 63 44 20 2171 64579 NT 10000 65 228 NT 207 66 449 NT 415 67 119 NT 10000 68 13 16 225 6917 8 3082 70 52 40 2630 71 1000 NT 10000 72 318 NT 8999 73 7 5 69 74 1410 4275 75 119 32 9226 76 237 NT 10000 77 25 16 547 78 550 NT 10000 79480 NT 8999 80 314 NT 8999 81 1223 NT 6708 82 379 NT 10000 83 12 4 176684 53 25 1322 85 98 63 1162 86 256 NT 2603 87 509 NT 10000 88 75 25 899989 452 NT 10000 90 38 25 1734 91 541 NT 10000 92 766 NT 8999 93 64 405000 94 551 NT 847 95 215 NT 774 96 68 50 2429 97 25 16 354 98 28 10 27599 15 16 180 100 238 NT 10000 101 48 25 4234 102 17 6 463 103 38 32 2280104 42 25 3604 105 20 20 2451 106 26 20 212 107 9 2 868 108 57 25 80 10946 25 65 110 52 32 350 111 28 16 153 112 95 20 122 113 50 63 90 114 224NT 3061 115 5000 NT 10000 116 22 13 61 117 24 8 42 118 19 5 1843 119 5113 3568 120 71 13 2867 121 15 13 42 122 865 NT 10000 123 44 79 10000 124422 NT 10000 125 901 NT 8999 126 95 100 75 127 55 20 40 128 18 4 1250129 111 100 1538 130 32 16 3438 131 75 79 131 132 125 79 7071 133 291 NT390 134 102 12 2722 135 90 40 10000 136 104 50 8999 137 50 25 891 138 3040 231 139 63 63 83 140 119 NT 1538 141 1034 NT 415 142 315 NT 2318 14381 79 150 144 87 63 537 145 45 32 70 146 27 16 137 147 85 63 2946 148129 NT 947 149 173 NT 142 150 92 40 5000 151 184 NT 504 152 125 NT 10000153 75 40 2645 154 241 NT 9654 155 33 16 8999 156 39 16 5000 157 69 165000 158 55 8 5000 159 45 8 2447 160 58 20 659 161 46 7 5317 162 43 55000 163 380 501 NT 164 289 200 722 165 852 NT 4637 166 465 NT 752 167411 631 2803 168 66 126 851 169 595 NT 1784 170 945 NT NT 171 780 NT NT172 450 NT NT 173 950 NT NT 174 729 NT NT 175 669 NT 1391 176 236 158923 177 339 NT NT 178 123 126 762 179 8999 NT NT 180 2300 NT NT 181 3564NT 8999 182 2198 NT 10000 183 5000 NT NT 184 1037 NT 879 185 8999 NT NT186 10000 NT NT 187 2283 NT NT 188 2608 NT NT 189 1600 NT NT 190 1300 NT5000 191 2658 NT NT 192 1015 NT NT 193 1156 NT 814 194 10000 NT NT 1951099 NT 646 196 10000 NT NT 197 1163 NT NT 198 1312 NT 2012 199 3777 NTNT 200 10000 NT 10000 201 1372 NT 10000 202 5000 NT 10000 203 5000 NT10000 204 50 20 169 205 3189 NT 10000 206 1266 NT 10000 207 8999 NT10000 208 2100 NT 10000 209 8999 NT 10000 210 3000 NT 10000 211 44 2510000 212 33 32 5000 213 56 50 10000 214 1227 NT 1077 215 5000 NT 10000219 404 NT 10000 220 500 NT 10000 221 2211 NT 10000 222 3621 NT 10000223 340 NT 10000 224 635 NT 10000 225 423 NT 10000 226 836 NT 10000 2271472 NT 10000 228 184 NT 10000 229 319 NT 10000 230 254 NT 10000 231 687 1613 232 52 7 2078 233 2100 NT 10000 234 10000 NT 10000 235 560 NT10000 236 10000 NT 10000 237 69 18 8247 238 243 NT 10000 239 7 4 173 2407 3 460 241 17 7 978 242 39 13 633 243 16 6 358 244 18 5 660 245 58 15369 246 11 11 208 247 650 NT 4399 248 170 NT 1400 249 NT NT NT 250 NT NTNT 251 25 2 1470 252 10000 NT 10000 253 5000 NT 10000 254 2200 NT 10000255 10000 NT 10000 256 10000 NT 10000 257 19 5 1843 258 46 25 927 259 83 335 260 90 16 8999 261 477 NT 10000 262 500 NT 10000 263 10000 NT10000 264 10000 NT 10000 265 8999 NT 10000 266 127 NT 8999 267 10000 NT10000 268 265 NT 10000 269 10000 NT 10000 270 1033 NT 10000 271 5000 NT10000 272 33 7 598 273 5000 NT 10000 274 61 16 8999 275 487 NT 10000 2762947 NT 10000 277 680 NT 10000 278 2274 NT 10000 279 23 10 1603 280 4163 71 281 8999 NT 10000 282 858 NT 1436 283 10 2 978 284 8 2 587 2851500 NT 10000 286 10000 NT 10000 287 1400 NT 10000 288 11 3 1606 2891800 NT 10000 290 19 7 2150 291 266 NT 10000 292 428 NT 10000 293 19 792186 294 4 3 125 295 24 10 1100 296 9 3 235 297 6 NT 261 298 9 NT 160299 15 NT 389 300 290 NT 2800 301 36 20 114 302 17 8 173 303 1700 NT10000 304 3100 NT 10000 305 7 NT 775 306 39 13 2300 307 10000 NT 10000308 26 5 1743 309 7 6 414 310 64 15 4996 311 7 3 312 312 79 11 3472 3137 3 128 314 13 4 958 315 38 10 2837 316 10 8 306 317 3 3 34 318 5 3 89319 18 7 537 320 4 2 54 321 29 10 816 322 10 5 378 323 25 4 2474 324 164 388 325 16 2 1662 326 8 4 151 327 103 50 5500 328 112 40 6345 32910000 NT 10000 330 10000 NT 10000 331 81 32 3791 332 114 63 10000 33310000 NT 10000 334 277 NT 10000 335 59 NT 3200 336 288 NT 10000 337 513NT 10000 338 1604 NT 10000 339 8999 NT 10000 340 1521 NT 10000 341 10000NT 10000 342 9486 NT 10000 343 36 NT 2900 344 1500 NT 10000 346 25 NT1800 347 3100 NT 10000 349 10000 NT 10000 351 1200 NT 10000 352 10000 NT3111 353 10000 NT 10000 355 10000 NT 10000 356 10000 NT 10000 358 230 NT10000 359 180 NT 10000 361 4399 NT 10000 362 1800 NT 2700 366 23 NT 1900367 15 3 839 369 19 NT 1200 370 84 7 7874 371 3400 NT 10000 372 109 NT8000 373 42 5 10000 374 73 12 1049 375 21 4 3186 376 17 NT 1591 377 17 22186 378 10 2 508 379 9 5 202 380 15 5 2039 381 10000 NT 10000 382 14 3854 383 13 4 920 384 10 5 1385 385 42 8 3688 386 940 NT 10000 387 16 9437 388 30 NT 694 389 22 14 492 390 190 NT 10000 391 28 NT 1200 399 570NT 10000 400 510 NT 10000 401 830 NT 10000 402 120 NT 10000 403 180 NT10000 404 19 NT 1200

Powder X-Ray Diffraction

[5-(4,6-Dimethyl-pyrimidin-2-yl)-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl]-(2-fluoro-6-[1,2,3]triazol-2-yl-phenyl)-methanone

Powder X-Ray Diffraction of the reference compound was performed on aPhilips X'PERT PRO with X'Celerator Cu detector equipped with a realtime multiple strips X-ray detection technology to obtain the X-raypowder patterns in FIG. 1 . The samples were scanned from 4° to 40° 2θ,at a step size 0.0167° 2θ and a time per step of 29.8450 seconds. Thetube voltage and current were 45 kV and 40 mA, respectively. The sampleswere placed onto zero background holders and analyzed on a spinningstage.

What is claimed is:
 1. A process for preparing a compound of Formula(I):

wherein: R¹ is selected from the group consisting of: A) phenylsubstituted or unsubstituted with one or two R^(a) members, andsubstituted in the ortho position with R^(b), wherein: R^(a) isindependently selected from the group consisting of —H, halo,—C₁₋₄alkyl, —C₁₋₄alkoxy, and —NO₂, wherein two adjacent R^(a) membersmay come together to form a six membered aromatic ring; R^(b) is amember selected from the group consisting of: a) halo, —C₁₋₄alkoxy,—C₁₋₄alkyl, —CF₃, —OCF₃, or —CN; b) 5-membered heteroaryl ringcontaining one oxygen or one sulfur members; c) 5-6 membered heteroarylring containing one, two or three nitrogen members, optionallycontaining one oxygen member, substituted or unsubstituted with halo or—C₁₋₄alkyl; and d) phenyl substituted or unsubstituted with halo, —CH₃,or —CF₃; B) pyridine substituted or unsubstituted with one or two R^(c)members and substituted with R^(d), wherein R^(d) is positioned adjacentto the point of attachment by R¹; R^(c) is C₁₋₄alkyl; R^(d) is a memberselected from the group consisting of: a) 5-6 membered heteroaryl ringselected from the group consisting of 1H-1,2,3-triazol-1-yl,2H-1,2,3-triazol-2-yl, 1H-pyrazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl,pyridinyl, 3-methyl-pyridin-2-yl,1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl), and pyrimidin-2-yl; b)—CF₃, —Br, and —C₁₋₄alkoxy; C) 5-membered heteroaryl ring selected fromthe group consisting of 2-methyl-1,3-thiazol-yl, 1H-pyrazol-5-yl,oxazole, isoxazolyl, thiophen-2-yl, and furan-2-yl, each substitutedwith phenyl substituted or unsubstituted with —F; and D) 5-13 memberedaryl or heteroaryl ring selected from the group consisting of3-methylfuran-2-yl, 9H-fluorene, quinoline, cinnoline,3-(1H-pyrrol-1-yl)thiophen-2-yl, 8-[1,2,3]-triazol-2-yl-naphthalen-1-yl,2,3-dihydro-1,4-benzodioxin-5-yl, 1H-indol-7-yl,4-fluoronaphthalen-1-yl, and naphthalen-1-yl; R² is selected from thegroup consisting of: A) 6-membered heteroaryl ring containing twonitrogen members substituted with one or more members independentlyselected from the group consisting of halo, —C₁₋₄alkyl, —CD₃, -D,—C₁₋₄alkoxy, cyclopropyl, morpholin-2-yl, —CO₂C₁₋₄alkyl, —CO₂H, —CH₂OH,—C(O)N(C₁₋₄alkyl)₂, —CF₃, —CN, —OH, —NO₂, —N(C₁₋₄alkyl)₂, phenyl,furan-2-yl, thiophen-2-yl, 1H-pyrazol-4-yl, and pyrrolidin-1-yl; B)pyridine substituted with one or two members independently selected fromthe group consisting of halo, —C₁₋₄alkyl, —C₁₋₄alkoxy, and —CF₃; C)9-membered heteroaryl ring selected from the group consisting ofbenzooxazol-2-yl, 6-fluoro-1,3-benzothiazole, 1,3-benzothiazole,6-methoxy-1,3-benzothiazole, 6-methyl-1,3-benzothiazole,6-chloro-benzothiazol-2-yl, and4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine; D) 10-memberedheteroaryl ring selected from the group consisting of quinoxalin-2-yl,3-methylquinoxalin-2-yl, 6,7-difluoroquinoxalin-2-yl,3-(trifluoromethyl)quinoxaline, quinoline, 4-methylquinoline, and6-fluoroquinazolin-2-yl; and E) 4-methyl-1,3,5-triazin-2-yl or2-methylpyrimidin-4(3H)-one, the process comprising reacting a compoundof Formula (I-a):

wherein, W is benzyl or BOC, with R¹CO₂H or R¹COCl to form a compound ofFormula (I-b):

deprotecting the compound of Formula (I-b) to form a compound of formula(I-c):

 and reacting the compound of Formula (I-c) with R²Cl to form thecompound of Formula (I).
 2. The process of claim 1, wherein the compoundof Formula (I-a) is reacted with R¹CO₂H under amide formationconditions.
 3. The process of claim 2, wherein the amide formationconditions comprise a dehydrating agent and base.
 4. The process ofclaim 3, wherein the dehydrating agent is HOBt/EDAC, CDI, HATU, or HOAT.5. The process of claim 3, wherein the base is DIPEA or TEA.
 6. Theprocess of claim 3, wherein the dehydrating agent is HATU and the baseis DIPEA.
 7. The process of claim 1, further comprising convertingR¹CO₂H to R¹COCl.
 8. The process of claim 7, comprising reacting R¹CO₂Hwith thionyl chloride.
 9. The process of claim 1, wherein thedeprotecting is performed using HCl, TFA, or p-toluenesulfonic acid. 10.The process of claim 1, further comprising reacting a compound ofFormula (I-d), wherein Wis Boc, with hydrogen gas in the presence of acatalyst to form the compound of Formula (I-b):


11. The process of claim 10, wherein the catalyst is palladium oncarbon.
 12. The process of claim 10, further comprising reacting2-benzyl-octahydro-pyrrolo[3,4-c]pyrrole with di-tert-butyl-dicarbonate.13. The process of claim 1, wherein the reaction with R²Cl is performedin the presence of a tertiary organic or inorganic base.
 14. The processof claim 13, wherein the base is Cs₂CO₃, Na₂CO₃, or TEA.
 15. A processfor preparing a compound of Formula (I):

wherein: R¹ is selected from the group consisting of: A) phenylsubstituted or unsubstituted with one or two R^(a) members, andsubstituted in the ortho position with R^(b), wherein: R^(a) isindependently selected from the group consisting of —H, halo,—C₁₋₄alkyl, —C₁₋₄alkoxy, and —NO₂, wherein two adjacent R^(a) membersmay come together to form a six membered aromatic ring; R^(b) is amember selected from the group consisting of: a) halo, —C₁₋₄alkoxy,—C₁₋₄alkyl, —CF₃, —OCF₃, or —CN; b) 5-membered heteroaryl ringcontaining one oxygen or one sulfur members; c) 5-6 membered heteroarylring containing one, two or three nitrogen members, optionallycontaining one oxygen member, substituted or unsubstituted with halo or—C₁₋₄alkyl; and d) phenyl substituted or unsubstituted with halo, —CH₃,or —CF₃; B) pyridine substituted or unsubstituted with one or two R^(c)members and substituted with R^(d), wherein R^(d) is positioned adjacentto the point of attachment by R¹; R^(c) is C₁₋₄alkyl; R^(d) is a memberselected from the group consisting of: a) 5-6 membered heteroaryl ringselected from the group consisting of 1H-1,2,3-triazol-1-yl,2H-1,2,3-triazol-2-yl, 1H-pyrazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl,pyridinyl, 3-methyl-pyridin-2-yl,1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl), and pyrimidin-2-yl; andb) —CF₃, —Br, and —C₁₋₄alkoxy; C) 5-membered heteroaryl ring selectedfrom the group consisting of 2-methyl-1,3-thiazol-yl, 1H-pyrazol-5-yl,oxazole, isoxazolyl, thiophen-2-yl, and furan-2-yl, each substitutedwith phenyl substituted or unsubstituted with —F; and D) 5-13 memberedaryl or heteroaryl ring selected from the group consisting of3-methylfuran-2-yl, 9H-fluorene, quinoline, cinnoline,3-(1H-pyrrol-1-yl)thiophen-2-yl, 8-[1,2,3]-triazol-2-yl-naphthalen-1-yl,2,3-dihydro-1,4-benzodioxin-5-yl, 1H-indol-7-yl,4-fluoronaphthalen-1-yl, and naphthalen-1-yl; R² is selected from thegroup consisting of: A) 6-membered heteroaryl ring containing twonitrogen members substituted with one or more members independentlyselected from the group consisting of halo, —C₁₋₄alkyl, —CD₃, -D,—C₁₋₄alkoxy, cyclopropyl, morpholin-2-yl, —CO₂C₁₋₄alkyl, —CO₂H, —CH₂OH,—C(O)N(C₁₋₄alkyl)₂, —CF₃, —CN, —OH, —NO₂, —N(C₁₋₄alkyl)₂, phenyl,furan-2-yl, thiophen-2-yl, 1H-pyrazol-4-yl, and pyrrolidin-1-yl; B)pyridine substituted with one or two members independently selected fromthe group consisting of halo, —C₁₋₄alkyl, —C₁₋₄alkoxy, and —CF₃; C)9-membered heteroaryl ring selected from the group consisting ofbenzooxazol-2-yl, 6-fluoro-1,3-benzothiazole, 1,3-benzothiazole,6-methoxy-1,3-benzothiazole, 6-methyl-1,3-benzothiazole,6-chloro-benzothiazol-2-yl, and4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine; D) 10-memberedheteroaryl ring selected from the group consisting of quinoxalin-2-yl,3-methylquinoxalin-2-yl, 6,7-difluoroquinoxalin-2-yl,3-(trifluoromethyl)quinoxaline, quinoline, 4-methylquinoline, and6-fluoroquinazolin-2-yl; and E) 4-methyl-1,3,5-triazin-2-yl or2-methylpyrimidin-4(3H)-one, the process comprising reacting a compoundof Formula (I-a):

wherein W is benzyl or BOC, with R²Cl to form a compound of Formula(I-e):

deprotecting the compound of Formula (I-e) to form a compound of Formula(I-f):

 and reacting the compound of Formula (I-f) with R¹CO₂H or R¹COCl toform the compound of Formula (I).
 16. The process of claim 15, whereinthe reaction with R²Cl is performed in the presence of a tertiaryorganic or inorganic base.
 17. The process of claim 16, wherein thetertiary organic or inorganic base is Cs₂CO₃, Na₂CO₃, or TEA.
 18. Theprocess of claim 15, further comprising converting R¹CO₂H to R¹COCl. 19.The process of claim 18, comprising reacting R¹CO₂H with thionylchloride.
 20. The process of claim 15, wherein when W is BOC, thedeprotecting is performed using HCl, TFA, or p-toluenesulfonic acid. 21.The process of claim 15, wherein when W is benzyl, the deprotecting isperformed using hydrogen gas in the presence of a catalyst.
 22. Theprocess of claim 21, wherein the catalyst is palladium on carbon.
 23. Aprocess for preparing a compound of Formula (I):

wherein: R¹ is selected from the group consisting of: A) phenylsubstituted or unsubstituted with one or two R^(a) members, andsubstituted in the ortho position with R^(b), wherein: R^(a) isindependently selected from the group consisting of —H, halo,—C₁₋₄alkyl, —C₁₋₄alkoxy, and —NO₂, wherein two adjacent R^(a) membersmay come together to form a six membered aromatic ring; R^(b) is amember selected from the group consisting of: a) halo, —C₁₋₄alkoxy,—C₁₋₄alkyl, —CF₃, —OCF₃, or —CN; b) 5-membered heteroaryl ringcontaining one oxygen or one sulfur members; c) 5-6 membered heteroarylring containing one, two or three nitrogen members, optionallycontaining one oxygen member, substituted or unsubstituted with halo or—C₁₋₄alkyl; and d) phenyl substituted or unsubstituted with halo, —CH₃,or —CF₃; B) pyridine substituted or unsubstituted with one or two R^(c)members and substituted with R^(d), wherein R^(d) is positioned adjacentto the point of attachment by R¹; R^(c) is C₁₋₄alkyl; R^(d) is a memberselected from the group consisting of: a) 5-6 membered heteroaryl ringselected from the group consisting of 1H-1,2,3-triazol-1-yl,2H-1,2,3-triazol-2-yl, 1H-pyrazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl,pyridinyl, 3-methyl-pyridin-2-yl,1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl), and pyrimidin-2-yl; andb) —CF₃, —Br, and —C₁₋₄alkoxy; C) 5-membered heteroaryl ring selectedfrom the group consisting of 2-methyl-1,3-thiazol-yl, 1H-pyrazol-5-yl,oxazole, isoxazolyl, thiophen-2-yl, and furan-2-yl, each substitutedwith phenyl substituted or unsubstituted with —F; and D) 5-13 memberedaryl or heteroaryl ring selected from the group consisting of3-methylfuran-2-yl, 9H-fluorene, quinoline, cinnoline,3-(1H-pyrrol-1-yl)thiophen-2-yl, 8-[1,2,3]-triazol-2-yl-naphthalen-1-yl,2,3-dihydro-1,4-benzodioxin-5-yl, 1H-indol-7-yl,4-fluoronaphthalen-1-yl, and naphthalen-1-yl; R² is selected from thegroup consisting of: A) 6-membered heteroaryl ring containing twonitrogen members substituted with one or more members independentlyselected from the group consisting of halo, —C₁₋₄alkyl, —CD₃, -D,—C₁₋₄alkoxy, cyclopropyl, morpholin-2-yl, —CO₂C₁₋₄alkyl, —CO₂H, —CH₂OH,—C(O)N(C₁₋₄alkyl)₂, —CF₃, —CN, —OH, —NO₂, —N(C₁₋₄alkyl)₂, phenyl,furan-2-yl, thiophen-2-yl, 1H-pyrazol-4-yl, and pyrrolidin-1-yl; B)pyridine substituted with one or two members independently selected fromthe group consisting of halo, —C₁₋₄alkyl, —C₁₋₄alkoxy, and —CF₃; C)9-membered heteroaryl ring selected from the group consisting ofbenzooxazol-2-yl, 6-fluoro-1,3-benzothiazole, 1,3-benzothiazole,6-methoxy-1,3-benzothiazole, 6-methyl-1,3-benzothiazole,6-chloro-benzothiazol-2-yl, and4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine; D) 10-memberedheteroaryl ring selected from the group consisting of quinoxalin-2-yl,3-methylquinoxalin-2-yl, 6,7-difluoroquinoxalin-2-yl,3-(trifluoromethyl)quinoxaline, quinoline, 4-methylquinoline, and6-fluoroquinazolin-2-yl; and E) 4-methyl-1,3,5-triazin-2-yl or2-methylpyrimidin-4(3H)-one, the process comprising reacting a compoundof Formula (I-f) with R¹CO₂H or R¹COCl to form the compound of Formula(I):


24. The process of claim 23, wherein the compound of Formula (I-f) isreacted with R¹CO₂H under amide formation conditions.
 25. The process ofclaim 24, wherein the amide formation conditions comprise a dehydratingagent and base.
 26. The process of claim 25, wherein the dehydratingagent is HOBt/EDAC, CDI, HATU, or HOAT.
 27. The process of claim 25,wherein the base is DIPEA or TEA.
 28. The process of claim 25, whereinthe dehydrating agent is HATU and the base is DIPEA.
 29. The process ofclaim 23, further comprising converting R¹CO₂H to R¹COCl.
 30. Theprocess of claim 29, comprising reacting R¹CO₂H with thionyl chloride.31. A process for preparing a compound of Formula (II):

wherein: R³ is phenyl substituted or unsubstituted with a memberindependently selected from the group consisting of —C₁₋₄alkoxy andphenyl; and R⁴ is a member selected from the group consisting of(5-trifluoromethyl)-pyridin-2-yl, (5-trifluoromethyl)-pyrimidin-2-yl,4,6-dimethylpyrimidin-2-yl, and quinoxalin-2-yl; the process comprisingreacting a compound of Formula (I-a):

wherein, W is benzyl or BOC, with R³SO₂Cl to form a compound of Formula(II-b);

deprotecting the compound of Formula (II-b); and reacting thedeprotected compound of Formula (II-b) with R⁴Cl to form the compound ofFormula (II).